The Race to Bash NASH: Emerging Targets and Drug Development in a Complex Liver Disease

This article references 398 other publications.

1. 1

   Chalasani, N.; Younossi, Z.; Lavine, J. E.; Charlton, M.; Cusi, K.; Rinella, M.; Harrison, S. A.; Brunt, E. M.; Sanyal, A. J. The Diagnosis and Management of Nonalcoholic Fatty Liver Disease: Practice Guidance from the American Association for the Study of Liver Diseases. Hepatology 2018, 67, 328– 357,  DOI: 10.1002/hep.29367

   [Crossref], [PubMed], [CAS], Google Scholar

   1

   The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases

   Chalasani Naga; Younossi Zobair; Lavine Joel E; Charlton Michael; Cusi Kenneth; Rinella Mary; Harrison Stephen A; Brunt Elizabeth M; Sanyal Arun J

   Hepatology (Baltimore, Md.) (2018), 67 (1), 328-357 ISSN:.

   There is no expanded citation for this reference.

   >> More from SciFinder ^®

   https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1cjot1WlsQ%253D%253D&md5=02f88048d1b753ccf27f6545776dd00e

   
2. 2

   Wong, R. J.; Aguilar, M.; Cheung, R.; Perumpail, R. B.; Harrison, S. A.; Younossi, Z. M.; Ahmed, A. Nonalcoholic Steatohepatitis is the Second Leading Etiology of Liver Disease Among Adults Awaiting Liver Transplantation in the United States. Gastroenterology 2015, 148, 547– 555,  DOI: 10.1053/j.gastro.2014.11.039

   [Crossref], [PubMed], [CAS], Google Scholar

   2

   Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States

   Wong Robert J; Aguilar Maria; Cheung Ramsey; Perumpail Ryan B; Ahmed Aijaz; Harrison Stephen A; Younossi Zobair M

   Gastroenterology (2015), 148 (3), 547-55 ISSN:.

   BACKGROUND & AIMS: Nonalcoholic steatohepatitis (NASH) has been predicted to become the leading indication for liver transplantation (LT) in the United States. However, few studies have evaluated changes in the etiology of liver diseases among patients awaiting LT, and none have focused on the effects of NASH on liver transplant waitlists in the United States. METHODS: We collected data from the United Network for Organ Sharing and Organ Procurement and Transplantation Network registry from 2004 through 2013, on liver transplant waitlist registrants with hepatitis C virus (HCV) infection, NASH, alcoholic liver disease (ALD), or a combination of HCV infection and ALD. We compared differences in survival within 90 days of registration (90-day survival) and probability of LT among patients with different diseases using Kaplan-Meier and multivariate logistic regression models. RESULTS: Between 2004 and 2013, new waitlist registrants with NASH increased by 170% (from 804 to 2174), with ALD increased by 45% (from 1400 to 2024), and with HCV increased by 14% (from 2887 to 3291); registrants with HCV and ALD decreased by 9% (from 880 to 803). In 2013, NASH became the second-leading disease among liver transplant waitlist registrants, after HCV. Patients with ALD had a significantly higher mean Model for End-Stage Liver Disease score at time of waitlist registration than other registrants. However, after multivariate adjustment, patients with ALD were less likely to die within 90 days when compared with patients with NASH (odds ratio [OR] = 0.77; 95% confidence interval [CI]: 0.67-0.89; P < .001); patients with HCV infection or HCV and ALD had similar odds for 90-day survival compared with NASH patients. Compared with patients with NASH, patients with HCV (OR = 1.45; 95% CI: 1.35-1.55; P < .001), ALD (OR = 1.15; 95% CI: 1.06-1.24; P < .001), or HCV and ALD (OR = 1.29; 95% CI: 1.18-1.42; P < .001) had higher odds for 90-day survival. CONCLUSIONS: Based on data from US adult LT databases, since 2004 the number of adults with NASH awaiting LTs has almost tripled. However, patients with NASH are less likely to undergo LT and less likely to survive for 90 days on the waitlist than patients with HCV, ALD, or HCV and ALD.

   >> More from SciFinder ^®

   https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2MzjsV2jsQ%253D%253D&md5=aee558facbbcd90e808becc7f46621b0

   
3. 3

   Mittal, S.; El-Serag, H. B.; Sada, Y. H.; Kanwal, F.; Duan, Z.; Temple, S.; May, S. B.; Kramer, J. R.; Richardson, P. A.; Davila, J. A. Hepatocellular Carcinoma in the Absence of Cirrhosis in United States Veterans is Associated with Nonalcoholic Fatty Liver Disease. Clin. Gastroenterol. Hepatol. 2016, 14, 124– 131,  DOI: 10.1016/j.cgh.2015.07.019

   [Crossref], [PubMed], [CAS], Google Scholar

   3

   Hepatocellular Carcinoma in the Absence of Cirrhosis in United States Veterans Is Associated With Nonalcoholic Fatty Liver Disease

   Mittal, Sahil; El-Serag, Hashem B.; Sada, Yvonne H.; Kanwal, Fasiha; Duan, Zhigang; Temple, Sarah; May, Sarah B.; Kramer, Jennifer R.; Richardson, Peter A.; Davila, Jessica A.

   Clinical Gastroenterology and Hepatology (2016), 14 (1), 124-131.e1CODEN: CGHLAW; ISSN:1542-3565. (Elsevier)

   Hepatocellular carcinoma (HCC) can develop in individuals without cirrhosis. We investigated risk factors for development of HCC in the absence of cirrhosis in a U. S. population. We identified a national cohort of 1500 patients with verified HCC during 2005 to 2010 in the U. S. Veterans Administration (VA) and reviewed their full VA medical records for evidence of cirrhosis and risk factors for HCC. Patients without cirrhosis were assigned to categories of level 1 evidence for no cirrhosis (very high probability) or level 2 evidence for no cirrhosis (high probability), which were based on findings from histol. analyses, lab. test results, markers of fibrosis from noninvasive tests, and imaging features. A total of 43 of the 1500 patients with HCC (2.9%) had level 1 evidence for no cirrhosis, and 151 (10.1%) had level 2 evidence for no cirrhosis; the remaining 1203 patients (80.1%) had confirmed cirrhosis. Compared with patients with HCC in presence of cirrhosis, greater proportions of patients with HCC without evidence of cirrhosis had metabolic syndrome, nonalcoholic fatty liver disease (NAFLD), or no identifiable risk factors. Patients with HCC without evidence of cirrhosis were less likely to have abused alc. or have hepatitis C virus infection than patients with cirrhosis. Patients with HCC and NAFLD (unadjusted odds ratio, 5.4; 95% confidence interval, 3.4-8.5) or metabolic syndrome (unadjusted odds ratio, 5.0; 95% confidence interval, 3.1-7.8) had more than 5-fold risk of having HCC in the absence of cirrhosis, compared with patients with HCV-related HCC. Approx. 13% of patients with HCC in the VA system do not appear to have cirrhosis. NAFLD and metabolic syndrome are the main risk factors for HCC in the absence of cirrhosis.

   >> More from SciFinder ^®

   https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsl2msrrE&md5=c4901fe5d85044a0c88138ccf61c48f8

   
4. 4

   Younossi, Z. M.; Koenig, A. B.; Abdelatif, D.; Fazel, Y.; Henry, L.; Wymer, M. Global Epidemiology of Nonalcoholic Fatty Liver Disease-Meta-Analytic Assessment of Prevalence, Incidence, and Outcomes. Hepatology 2016, 64, 73– 84,  DOI: 10.1002/hep.28431

   [Crossref], [PubMed], [CAS], Google Scholar

   4

   Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes

   Younossi Zobair M; Wymer Mark; Younossi Zobair M; Koenig Aaron B; Abdelatif Dinan; Fazel Yousef; Wymer Mark; Henry Linda

   Hepatology (Baltimore, Md.) (2016), 64 (1), 73-84 ISSN:.

   UNLABELLED: Nonalcoholic fatty liver disease (NAFLD) is a major cause of liver disease worldwide. We estimated the global prevalence, incidence, progression, and outcomes of NAFLD and nonalcoholic steatohepatitis (NASH). PubMed/MEDLINE were searched from 1989 to 2015 for terms involving epidemiology and progression of NAFLD. Exclusions included selected groups (studies that exclusively enrolled morbidly obese or diabetics or pediatric) and no data on alcohol consumption or other liver diseases. Incidence of hepatocellular carcinoma (HCC), cirrhosis, overall mortality, and liver-related mortality were determined. NASH required histological diagnosis. All studies were reviewed by three independent investigators. Analysis was stratified by region, diagnostic technique, biopsy indication, and study population. We used random-effects models to provide point estimates (95% confidence interval [CI]) of prevalence, incidence, mortality and incidence rate ratios, and metaregression with subgroup analysis to account for heterogeneity. Of 729 studies, 86 were included with a sample size of 8,515,431 from 22 countries. Global prevalence of NAFLD is 25.24% (95% CI: 22.10-28.65) with highest prevalence in the Middle East and South America and lowest in Africa. Metabolic comorbidities associated with NAFLD included obesity (51.34%; 95% CI: 41.38-61.20), type 2 diabetes (22.51%; 95% CI: 17.92-27.89), hyperlipidemia (69.16%; 95% CI: 49.91-83.46%), hypertension (39.34%; 95% CI: 33.15-45.88), and metabolic syndrome (42.54%; 95% CI: 30.06-56.05). Fibrosis progression proportion, and mean annual rate of progression in NASH were 40.76% (95% CI: 34.69-47.13) and 0.09 (95% CI: 0.06-0.12). HCC incidence among NAFLD patients was 0.44 per 1,000 person-years (range, 0.29-0.66). Liver-specific mortality and overall mortality among NAFLD and NASH were 0.77 per 1,000 (range, 0.33-1.77) and 11.77 per 1,000 person-years (range, 7.10-19.53) and 15.44 per 1,000 (range, 11.72-20.34) and 25.56 per 1,000 person-years (range, 6.29-103.80). Incidence risk ratios for liver-specific and overall mortality for NAFLD were 1.94 (range, 1.28-2.92) and 1.05 (range, 0.70-1.56). CONCLUSIONS: As the global epidemic of obesity fuels metabolic conditions, the clinical and economic burden of NAFLD will become enormous. (Hepatology 2016;64:73-84).

   >> More from SciFinder ^®

   https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC28rkvF2nsQ%253D%253D&md5=9f56908402e55f782c89df147ee89796

   
5. 5

   Castera, L.; Friedrich-Rust, M.; Loomba, R. Noninvasive Assessment of Liver Disease in Patients With Nonalcoholic Fatty Liver Disease. Gastroenterology 2019, 156, 1264– 1281,  DOI: 10.1053/j.gastro.2018.12.036

   [Crossref], [PubMed], [CAS], Google Scholar

   5

   Noninvasive Assessment of Liver Disease in Patients With Nonalcoholic Fatty Liver Disease

   Castera Laurent; Friedrich-Rust Mireen; Loomba Rohit

   Gastroenterology (2019), 156 (5), 1264-1281.e4 ISSN:.

   Nonalcoholic fatty liver disease (NAFLD) is estimated to afflict approximately 1 billion individuals worldwide. In a subset of NAFLD patients, who have the progressive form of NAFLD termed nonalcoholic steatohepatitis (NASH), it can progress to advanced fibrosis, cirrhosis, hepatocellular carcinoma, and liver-related morbidity and mortality. NASH is typically characterized by a specific pattern on liver histology, including steatosis, lobular inflammation, and ballooning with or without peri-sinusoidal fibrosis. Thus, key issues in NAFLD patients are the differentiation of NASH from simple steatosis and identification of advanced hepatic fibrosis. Until now, liver biopsy has been the gold standard for identifying these 2 critical end points, but has well-known limitations, including invasiveness; rare but potentially life-threatening complications; poor acceptability; sampling variability; and cost. Furthermore, due to the epidemic proportion of individuals with NAFLD worldwide, liver biopsy evaluation is impractical, and noninvasive assessment for the diagnosis of NASH and fibrosis is needed. Although much of the work remains to be done in establishing cost-effective strategies for screening for NASH, advanced fibrosis, and cirrhosis, in this review, we summarize the current state of the noninvasive assessment of liver disease in NAFLD, and we provide an expert synthesis of how these noninvasive tools could be utilized in clinical practice. Finally, we also list the key areas of research priorities in this area to move forward clinical practice.

   >> More from SciFinder ^®

   https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3cjjtFKntg%253D%253D&md5=a0baa33216078d280931be9b4193beaa

   
6. 6

   Brunt, E. M.; Janney, C. G.; Bisceglie, A. M.; Neuschwander-Tetri, B. A.; Bacon, B. R. Nonalcoholic Steatohepatitis: A Proposal for Grading and Staging the Histological Lesions. Am. J. Gastroenterol. 1999, 94, 2467– 2474,  DOI: 10.1111/j.1572-0241.1999.01377.x

   [Crossref], [PubMed], [CAS], Google Scholar

   6

   Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions

   Brunt E M; Janney C G; Di Bisceglie A M; Neuschwander-Tetri B A; Bacon B R

   The American journal of gastroenterology (1999), 94 (9), 2467-74 ISSN:0002-9270.

   OBJECTIVE: Steatohepatitis is a morphological pattern of liver injury that may be seen in alcoholic or nonalcoholic liver disease. This pattern may occur with obesity, diabetes, the use of certain drugs, or the cause may be idiopathic. The well-recognized histopathological features of nonalcoholic steatohepatitis (NASH) include hepatocellular steatosis and ballooning, mixed acute and chronic lobular inflammation, and zone 3 perisinusoidal fibrosis. Currently, there are no systems for grading necroinflammatory activity or for staging fibrosis as exist for various other forms of chronic liver disease. The purpose of this study was to develop such a grading and staging system and was based on review of liver biopsies from 51 patients with nonalcoholic steatohepatitis from Saint Louis University Health Sciences Center. METHODS: For determination of grade, 10 histological variables of activity were initially analyzed; an overall impression of mild, moderate, and severe was made and the variables considered to be most significant were used to develop the necroinflammatory grade. RESULTS: The histological lesions considered to be significant were: steatosis, ballooning, and intra-acinar and portal inflammation. A staging score was developed to reflect both location and extent of fibrosis. The fibrosis score was derived from the extent of zone 3 perisinusoidal fibrosis with possible additional portal/periportal fibrosis and architectural remodeling. Fibrosis stages are as follows: Stage 1, zone 3 perisinusoidal fibrosis; Stage 2, as above with portal fibrosis; Stage 3, as above with bridging fibrosis; and Stage 4, cirrhosis. CONCLUSION: We propose a grading and staging system that reflects the unique histological features of nonalcoholic steatohepatitis.

   >> More from SciFinder ^®

   https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK1MvhtFyisw%253D%253D&md5=ec8d1234e43df7e8e50dc8d42fc21856

   
7. 7

   Bedossa, P.; Poitou, C.; Veyrie, N.; Bouillot, J. L.; Basdevant, A.; Paradis, V.; Tordjman, J.; Clement, K. Histopathological Algorithm and Scoring System for Evaluation of Liver Lesions in Morbidly Obese Patients. Hepatology 2012, 56, 1751– 1759,  DOI: 10.1002/hep.25889

   [Crossref], [PubMed], [CAS], Google Scholar

   7

   Histopathological algorithm and scoring system for evaluation of liver lesions in morbidly obese patients

   Bedossa Pierre; Poitou Christine; Veyrie Nicolas; Bouillot Jean-Luc; Basdevant Arnaud; Paradis Valerie; Tordjman Joan; Clement Karine

   Hepatology (Baltimore, Md.) (2012), 56 (5), 1751-9 ISSN:.

   UNLABELLED: Nonalcoholic fatty liver disease (NAFLD) is highly prevalent and being overweight is a significant risk factor. The aim was to build an algorithm along with a scoring system for histopathologic classification of liver lesions that covers the entire spectrum of lesions in morbidly obese patients. A cohort of 679 obese patients undergoing liver biopsy at the time of bariatric surgery was studied. An algorithm for segregating lesions into normal liver, NAFLD, or nonalcoholic steatohepatitis (NASH) was built based on semiquantitative evaluation of steatosis, hepatocellular ballooning, and lobular inflammation. For each case, the SAF score was created including the semiquantitative scoring of steatosis (S), activity (A), and fibrosis (F). Based on the algorithm, 230 obese patients (34%) were categorized as NASH, 291 (43%) as NAFLD without NASH, and 158 (23%) as not NAFLD. The activity score (ballooning + lobular inflammation) enabled discriminating NASH because all patients with NASH had A ≥ 2, whereas no patients with A < 2 had NASH. This score was closely correlated with both alanine aminotransferase (ALT) and aspartate aminotransferase (AST) (P < 0.0001, analysis of variance [ANOVA]). Comparison of transaminase levels between patients with normal liver and pure steatosis did not reveal significant differences, thus lending support to the proposal not to include steatosis in the activity score but to report it separately in the SAF score. In the validation series, the interobserver agreement for the diagnosis of NASH was excellent (κ = 0.80) between liver pathologists. There was no discrepancy between the initial diagnosis and the diagnosis proposed using the algorithm. CONCLUSION: We propose a simple but robust algorithm for categorizing liver lesions in NAFLD patients. Because liver lesions in obese patients may display a continuous spectrum of histologic lesions, we suggest describing liver lesions using the SAF score.

   >> More from SciFinder ^®

   https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC38jisFOnsw%253D%253D&md5=b4078bf2dd663c5948e7f14cd074f32e

   
8. 8

   Eslam, M.; Valenti, L.; Romeo, S. Genetics and Epigenetics of NAFLD and NASH: Clinical Impact. J. Hepatol. 2018, 68, 268– 279,  DOI: 10.1016/j.jhep.2017.09.003

   [Crossref], [PubMed], [CAS], Google Scholar

   8

   Genetics and epigenetics of NAFLD and NASH: Clinical impact

   Eslam, Mohammed; Valenti, Luca; Romeo, Stefano

   Journal of Hepatology (2018), 68 (2), 268-279CODEN: JOHEEC; ISSN:0168-8278. (Elsevier B.V.)

   Non-alc. fatty liver disease (NAFLD) is now recognized as the most common liver disease worldwide. It encompasses a broad spectrum of conditions, from simple steatosis, through non-alc. steatohepatitis, to fibrosis and ultimately cirrhosis and hepatocellular carcinoma. A hallmark of NAFLD is the substantial inter-patient variation in disease progression. NAFLD is considered a complex disease trait such that interactions between the environment and a susceptible polygenic host background det. disease phenotype and influence progression. Recent years have witnessed multiple genome-wide assocn. and large candidate gene studies, which have enriched our understanding of the genetic basis of NAFLD. Notably, the I148M PNPLA3 variant has been identified as the major common genetic determinant of NAFLD. Variants with moderate effect size in TM6SF2, MBOAT7 and GCKR have also been shown to have a significant contribution. The premise for this review is to discuss the status of research into important genetic and epigenetic modifiers of NAFLD progression. The potential to translate the accumulating wealth of genetic data into the design of novel therapeutics and the clin. implementation of diagnostic/prognostic biomarkers will be explored. Finally, personalised medicine and the opportunities for future research and challenges in the immediate post genetics era will be illustrated and discussed.

   >> More from SciFinder ^®

   https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhslymt7vO&md5=6cd489bbe8db3da20a4ffa4b646b3794

   
9. 9

   Mohamad, B.; Shah, V.; Onyshchenko, M.; Elshamy, M.; Aucejo, F.; Lopez, R.; Hanouneh, I. A.; Alhaddad, R.; Alkhouri, N. Characterization of Hepatocellular Carcinoma (HCC) in Non-Alcoholic Fatty Liver Disease (NAFLD) Patients without Cirrhosis. Hepatol. Int. 2016, 10, 632– 639,  DOI: 10.1007/s12072-015-9679-0

   [Crossref], [PubMed], [CAS], Google Scholar

   9

   Characterization of hepatocellular carcinoma (HCC) in non-alcoholic fatty liver disease (NAFLD) patients without cirrhosis

   Mohamad Bashar; Shah Vaishal; Onyshchenko Mykola; Elshamy Mohammed; Aucejo Federico; Hanouneh Ibrahim A; Alhaddad Razan; Alkhouri Naim; Lopez Rocio

   Hepatology international (2016), 10 (4), 632-9 ISSN:.

   BACKGROUND: The incidence of hepatocellular carcinoma (HCC) has increased significantly in United States over the last few decades in parallel with the epidemic of nonalcoholic fatty liver disease (NAFLD). Limited data suggests that HCC could arise in steatotic liver without the presence of cirrhosis. The present study was conducted to characterize patients with NAFLD presenting with HCC in non-cirrhotic liver (NCL) compared to the NAFLD- HCC patients in association with cirrhotic liver (CL). METHODS: A retrospective analysis of all patients diagnosed with HCC and NAFLD diagnosis seen at our institution between 2003 and 2012 was done. The patients were characterized based on demographic and clinical variables as well as histological and tumor features. Comparisons between the NCL and CL groups were done using analysis of variance (ANOVA) or the non-parametric Kruskal-Wallis tests and Pearson's chi-square tests or Fisher's Exact tests as appropriate. P value of <0.05 was considered statistically significant. RESULTS: Thirty-six patients with NAFLD and HCC in NCL (HCC-NCL group) were identified and compared to 47 patients with NAFLD-HCC and Liver Cirrhosis (HCC-LC group). Liver fibrosis was not present in 55.9 % of patients in the HCC-NCL group (F0), stage 1 was present in 17.6 %, stage 2 in 8.8 % and stage 3 in 17.6 %. Lobular inflammation was present in 63.6 % of non-cirrhotic patients. Patients in the HCC-NCL were older (67.5 ± 12.3 vs. 62.7 ± 8.1 years), and less likely to be obese (52 % vs. 83 %) or have type 2 diabetes (38 % vs. 83 %), with p value <0.05 for all. More importantly, compared with the HCC-CL group, those in the HCC-NCL group were more likely to present with a single nodule (80.6 % vs. 52.2 %), larger nodule size (>5 cm) (77.8 % vs. 10.6 %), and receive hepatic resection as the modality of HCC treatment (66.7 % vs. 17 %); and were less likely to receive loco-regional therapy (22.3 % vs. 61.7 %) or orthotopic liver transplantation (OLT) (0 % vs. 72.3 %), with p value <0.001 for all. Furthermore, 86 % of patients without cirrhosis had HCC recurrence compared to only 14 % in patients with cirrhosis (p < 0.001). Unadjusted analysis indicates that non-cirrhotics had worse survival with mortality rate of 47 % vs. 28 % in CL group (p = 0.03); however this difference in survival between two groups was not significant after adjusting for age or OLT (p > 0.05). CONCLUSION: Patients with HCC in the absence of liver cirrhosis are more likely to present at an older age with larger tumor and have higher rates of tumor recurrence. Studies to assess the cost-effectiveness of HCC surveillance in this group should be conducted.

   >> More from SciFinder ^®

   https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC28vhtFClsw%253D%253D&md5=816354903bd52d69e85927be8097c701

   
10. 10

    Glass, L. M.; Hunt, C. M.; Fuchs, M.; Su, G. L. Comorbidities and Nonalcoholic Fatty Liver Disease: The Chicken, the Egg, or Both?. Fed. Pract. 2019, 36, 64– 71

    [PubMed], [CAS], Google Scholar

    10

    Comorbidities and Nonalcoholic Fatty Liver Disease: The Chicken, the Egg, or Both?

    Glass Lisa M; Hunt Christine M; Fuchs Michael; Su Grace L

    Federal practitioner : for the health care professionals of the VA, DoD, and PHS (2019), 36 (2), 64-71 ISSN:1078-4497.

    Improvement in NAFLD may lead to improvement of metabolic syndrome, cardiovascular disease, and malignancy and vice versa.

    >> More from SciFinder ^®

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3cbjslGlsg%253D%253D&md5=3227a352e953ed93d44c82e03bf2ad78

    
11. 11

    Subichin, M.; Clanton, J.; Makuszewski, M.; Bohon, A.; Zografakis, J. G.; Dan, A. Liver Disease in the Morbidly Obese: A Review of 1000 Consecutive Patients Undergoing Weight Loss Surgery. Surg. Obes. Relat. Dis. 2015, 11, 137– 141,  DOI: 10.1016/j.soard.2014.06.015

    [Crossref], [PubMed], [CAS], Google Scholar

    11

    Liver disease in the morbidly obese: a review of 1000 consecutive patients undergoing weight loss surgery

    Subichin Michael; Clanton Jesse; Makuszewski Marta; Bohon Ashley; Zografakis John G; Dan Adrian

    Surgery for obesity and related diseases : official journal of the American Society for Bariatric Surgery (2015), 11 (1), 137-41 ISSN:.

    BACKGROUND: Liver disease among the morbidly obese is increasingly prevalent, contributing to significant morbidity. Obesity-related liver pathologies including nonalcoholic steatohepatitis (NASH) have become a leading cause for liver transplant. However, risk factors for developing severe liver disease in the morbidly obese remain unknown. The objective of this study was to determine the frequency of abnormal liver pathology and any relationship to patient-related factors. METHODS: One thousand consecutive patients undergoing weight loss surgery were reviewed. All patients had a liver biopsy at the time of surgery. Frequency of benign pathology, steatosis, NASH, and fibrosis on pathologic examination of liver biopsy specimens were recorded. Pathologic findings were compared and analyzed to age and body mass index (BMI) of all patients. RESULTS: All patients in the study population had a BMI>35 kg/m2. Of these patients, 80.2% had liver disease related to obesity on pathology, including 65.9% with steatosis (grade 1-3), and 14.3% with NASH and/or fibrosis. Mean BMI of patients with liver disease was 48.1 compared to a BMI of 47.7 with benign pathology (P=.523). Mean age of patients with and without abnormal pathology was 48.3 and 47.3, respectively (P=.294). CONCLUSION: Liver disease is highly prevalent in the obese, but is not associated with increased age or BMI. Although all morbidly obese patients appear at significant risk for developing severe liver pathology, further risk factors are unknown.

    >> More from SciFinder ^®

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2MrnvVSiug%253D%253D&md5=ce96150919af39e87bfb869545b5a117

    
12. 12

    Leite, N. C.; Salles, G. F.; Araujo, A. L.; Villela-Nogueira, C. A.; Cardoso, C. R. Prevalence and Associated Factors of Non-Alcoholic Fatty Liver Disease in Patients with Type-2 Diabetes Mellitus. Liver Int. 2009, 29, 113– 119,  DOI: 10.1111/j.1478-3231.2008.01718.x

    [Crossref], [PubMed], [CAS], Google Scholar

    12

    Prevalence and associated factors of non-alcoholic fatty liver disease in patients with type-2 diabetes mellitus

    Leite, Nathalie C.; Salles, Gil F.; Araujo, Antonio L. E.; Villela-Nogueira, Cristiane A.; Cardoso, Claudia R. L.

    Liver International (2009), 29 (1), 113-119CODEN: LIINCM; ISSN:1478-3223. (Wiley-Blackwell)

    Background/Aims: Diabetic patients have an increased prevalence and severity of nonalcoholic fatty liver disease (NAFLD). We aimed to investigate the prevalence and the factors assocd. with the presence of ultrasonog. NAFLD in type-2 diabetic individuals. Methods: In a cross-sectional design study, 180 type-2 diabetic patients were submitted to a complete clin. and lab. evaluation and abdominal ultrasonog. for NAFLD detection and grading. Statistical anal. included bivariate tests, anal. of variance (ANOVA, for increasing severity of steatosis) and multivariate logistic regression. Results: The prevalence of ultrasonog. NAFLD was 69.4% [95% confidence interval (CI): 58.3-82.7%]. Patients with NAFLD were more obese, had a higher waist circumference and serum triglyceride and alanine aminotransferase (ALT) levels than those without steatosis. Neither diabetic degenerative complication, nor glycemic control was assocd. with liver steatosis. On multivariate anal., a high serum triglycerides level [> 2.82 mmol/L, odds ratio (OR): 3.7-4.1, 95% CI: 1.2-13.3] and a high-normal ALT level (≥ 40 U/L, OR: 2.5-2.7, 95% CI: 1.2-5.9) were independently assocd. with hepatic steatosis, together with either the presence of obesity (OR: 7.1, 95% CI: 3.0-17.0) or of increased waist circumference (OR: 4.8, 95% CI: 1.9-12.2). Conclusions: Type-2 diabetic patients have a high prevalence of ultrasonog. NAFLD and its presence is assocd. with obesity, mainly abdominal, hypertriglyceridemia and high-normal ALT levels. Nonalcoholic fatty liver disease in diabetic patients may develop and progress independent of the diabetes progression itself.

    >> More from SciFinder ^®

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhvVGmtLk%253D&md5=2ac6fc272c22e714515cae847e98805e

    
13. 13

    Ekstedt, M.; Hagstrom, H.; Nasr, P.; Fredrikson, M.; Stal, P.; Kechagias, S.; Hultcrantz, R. Fibrosis Stage is the Strongest Predictor for Disease-Specific Mortality in NAFLD after up to 33 Years of Follow-Up. Hepatology 2015, 61, 1547– 1554,  DOI: 10.1002/hep.27368

    [Crossref], [PubMed], [CAS], Google Scholar

    13

    Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up

    Ekstedt, Mattias; Hagstroem, Hannes; Nasr, Patrik; Fredrikson, Mats; Stal, Per; Kechagias, Stergios; Hultcrantz, Rolf

    Hepatology (Hoboken, NJ, United States) (2015), 61 (5), 1547-1554CODEN: HPTLD9; ISSN:0270-9139. (John Wiley & Sons, Inc.)

    Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in the Western world, strongly assocd. with insulin resistance and the metabolic syndrome. Nonalcoholic steatohepatitis, i.e., fatty liver accompanied by necroinflammatory changes, is mostly defined by the NAFLD activity score (NAS). The aim of the current study was to det. disease-specific mortality in NAFLD, and evaluate the NAS and fibrosis stage as prognostic markers for overall and disease-specific mortality. In a cohort study, data from 229 well-characterized patients with biopsy-proven NAFLD were collected. Mean follow-up was 26.4 (±5.6, range 6-33) years. A ref. population was obtained from the National Registry of Population, and information on time and cause of death were obtained from the Registry of Causes of Death. NAFLD patients had an increased mortality compared with the ref. population (hazard ratio [HR] 1.29, confidence interval [CI] 1.04-1.59, P = 0.020), with increased risk of cardiovascular disease (HR 1.55, CI 1.11-2.15, P = 0.01), hepatocellular carcinoma (HR 6.55, CI 2.14-20.03, P = 0.001), infectious disease (HR 2.71, CI 1.02-7.26, P = 0.046), and cirrhosis (HR 3.2, CI 1.05-9.81, P = 0.041). Overall mortality was not increased in patients with NAS 5-8 and fibrosis stage 0-2 (HR 1.41, CI 0.97-2.06, P = 0.07), whereas patients with fibrosis stage 3-4, irresp. of NAS, had increased mortality (HR 3.3, CI 2.27-4.76, P < 0.001). Conclusion: NAFLD patients have increased risk of death, with a high risk of death from cardiovascular disease and liver-related disease. The NAS was not able to predict overall mortality, whereas fibrosis stage predicted both overall and disease-specific mortality.

    >> More from SciFinder ^®

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXmslWlt7Y%253D&md5=ec1c657e5b9c76fa67af4ee93172ba83

    
14. 14

    Vilar-Gomez, E.; Martinez-Perez, Y.; Calzadilla-Bertot, L.; Torres-Gonzalez, A.; Gra-Oramas, B.; Gonzalez-Fabian, L.; Friedman, S. L.; Diago, M.; Romero-Gomez, M. Weight Loss Through Lifestyle Modification Significantly Reduces Features of Nonalcoholic Steatohepatitis. Gastroenterology 2015, 149, 367– 378,  DOI: 10.1053/j.gastro.2015.04.005

    [Crossref], [PubMed], [CAS], Google Scholar

    14

    Weight Loss Through Lifestyle Modification Significantly Reduces Features of Nonalcoholic Steatohepatitis

    Vilar-Gomez Eduardo; Martinez-Perez Yadina; Calzadilla-Bertot Luis; Torres-Gonzalez Ana; Gra-Oramas Bienvenido; Gonzalez-Fabian Licet; Friedman Scott L; Diago Moises; Romero-Gomez Manuel

    Gastroenterology (2015), 149 (2), 367-78.e5; quiz e14-5 ISSN:.

    BACKGROUND & AIMS: It is not clear how weight loss affects histologic features of liver in patients with nonalcoholic steatohepatitis (NASH). We examined the association between the magnitude of weight loss through lifestyle modifications and changes in histologic features of NASH. METHODS: We conducted a prospective study of 293 patients with histologically proven NASH who were encouraged to adopt recommended lifestyle changes to reduce their weight over 52 weeks, from June 2009 through May 2013, at a tertiary medical center in Havana, Cuba. Liver biopsies were collected when the study began and at week 52 of the diet and were analyzed histologically. RESULTS: Paired liver biopsies were available from 261 patients. Among 293 patients who underwent lifestyle changes for 52 weeks, 72 (25%) achieved resolution of steatohepatitis, 138 (47%) had reductions in nonalcoholic fatty liver disease activity score (NAS), and 56 (19%) had regression of fibrosis. At week fifty-two, 88 subjects (30%) had lost ≥5% of their weight. Degree of weight loss was independently associated with improvements in all NASH-related histologic parameters (odds ratios = 1.1-2.0; P < .01). A higher proportion of subjects with ≥5% weight loss had NASH resolution (51 of 88 [58%]) and a 2-point reduction in NAS (72 of 88 [82%]) than subjects who lost <5% of their weight (P < .001). All patients who lost ≥10% of their weight had reductions NAS, 90% had resolution of NASH, and 45% had regression of fibrosis. All patients who lost 7%-10% of their weight and had few risk factors also had reduced NAS. In patients with baseline characteristics that included female sex, body mass index ≥35, fasting glucose >5.5 mmol/L, and many ballooned cells, NAS scores decreased significantly with weight reductions ≥10%. CONCLUSIONS: A greater extent of weight loss, induced by lifestyle changes, is associated with the level of improvement in histologic features of NASH. The highest rates of NAS reduction, NASH resolution, and fibrosis regression occurred in patients with weight losses ≥10%.

    >> More from SciFinder ^®

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2Mjjt1elsQ%253D%253D&md5=785bf888619ea9d5aaf95ca49c5aa355

    
15. 15

    Lassailly, G.; Caiazzo, R.; Buob, D.; Pigeyre, M.; Verkindt, H.; Labreuche, J.; Raverdy, V.; Leteurtre, E.; Dharancy, S.; Louvet, A.; Romon, M.; Duhamel, A.; Pattou, F.; Mathurin, P. Bariatric Surgery Reduces Features of Nonalcoholic Steatohepatitis in Morbidly Obese Patients. Gastroenterology 2015, 149, 379– 388,  DOI: 10.1053/j.gastro.2015.04.014

    [Crossref], [PubMed], [CAS], Google Scholar

    15

    Bariatric Surgery Reduces Features of Nonalcoholic Steatohepatitis in Morbidly Obese Patients

    Lassailly Guillaume; Dharancy Sebastien; Louvet Alexandre; Caiazzo Robert; Buob David; Leteurtre Emmanuelle; Pigeyre Marie; Romon Monique; Verkindt Helene; Raverdy Violeta; Labreuche Julien; Duhamel Alain; Pattou Francois; Mathurin Philippe

    Gastroenterology (2015), 149 (2), 379-88; quiz e15-6 ISSN:.

    BACKGROUND & AIMS: The effects of bariatric surgery in patients with nonalcoholic fatty liver disease (NASH) are not well established. We performed a prospective study to determine the biological and clinical effects of bariatric surgery in patients with NASH. METHODS: From May 1994 through May 2013, one hundred and nine morbidly obese patients with biopsy-proven NASH underwent bariatric surgery at the University Hospital of Lille, France (the Lille Bariatric Cohort). Clinical, biological, and histologic data were collected before and 1 year after surgery. RESULTS: One year after surgery, NASH had disappeared from 85% of the patients (95% confidence interval [CI]: 75.8%-92.2%). Compared with before surgery, patients had significant reductions in mean ± SD body mass index (BMI, from 49.3 ± 8.2 to 37.4 ± 7) and level of alanine aminotransferase (from 52.1 ± 25.7 IU/L to 25.1 ± 20 IU/L); mean levels of γ-glutamyltransferases were reduced from 51 IU/L before surgery (interquartile range [IQR], 34-87 IU/L) to 23 IU/L afterward (IQR, 14-33 IU/L) and mean insulin resistance index values were reduced from 3.6 ± 0.5 to 2.9 ± 0.5 (P < .01 for each comparison). NASH disappeared from a higher proportion of patients with mild NASH before surgery (94%) than severe NASH (70%) (P < .05) according to Brunt score. In histologic analysis, steatosis was detected in 60% of the tissue before surgery (IQR, 40%-80%) but only 10% 1 year after surgery (IQR, 2.5%-21.3%); the mean nonalcoholic fatty liver disease score was reduced from 5 (IQR, 4-5) to 1 (IQR, 1-2) (each P < .001). Hepatocellular ballooning was reduced in 84.2% of samples (n = 69; 95% CI: 74.4-91.3) and lobular inflammation in 67.1% (n = 55; 95% CI: 55.8-77.1). According to Metavir scores, fibrosis was reduced in 33.8% of patients (95% CI: 23.6%-45.2%). Patients whose NASH persisted 1 year after surgery (n = 12) had lost significantly less weight (change in BMI, 9.1 ± 1.5) than those without NASH (change in BMI, 12.3 ± 0.6) (P = .005). Patients who underwent laparoscopic gastric banding lost less weight (change in BMI, 6.4 ± 0.7) than those who underwent gastric bypass (change in BMI, 14.0 ± 0.5) (P < .0001), and a higher proportion had persistent NASH (30.4% vs 7.6% of those with gastric bypass; P = .015). CONCLUSIONS: Bariatric surgery induced the disappearance of NASH from nearly 85% of patients and reduced the pathologic features of the disease after 1 year of follow-up. It could be a therapeutic option for appropriate morbidly obese patients with NASH who do not respond to lifestyle modifications. More studies are needed to determine the long-term effects of bariatric surgery in morbidly obese patients with NASH.

    >> More from SciFinder ^®

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2Mjotlaltg%253D%253D&md5=60574c6cac5bfbda82477628cacc47e9

    
16. 16

    Desvergne, B.; Wahli, W. Peroxisome Proliferator-Activated Receptors: Nuclear Control of Metabolism. Endocr. Rev. 1999, 20, 649– 688,  DOI: 10.1210/edrv.20.5.0380

    [Crossref], [PubMed], [CAS], Google Scholar

    16

    Peroxisome proliferator-activated receptors: nuclear control of metabolism

    Desvergne, Beatrice; Wahli, Walter

    Endocrine Reviews (1999), 20 (5), 649-688CODEN: ERVIDP; ISSN:0163-769X. (Endocrine Society)

    A review, with 408 refs., on the mol. and physiol. aspects of peroxisome proliferator-activated receptors (PPAR). Mol. aspects included: PPAR isotype identity, genomic organization, and chromosomal localization; DNA binding properties; ligand binding properties; pathways for activation; and PPAR transactivation properties. Physiol. aspects included: differential expression of PPAR mRNAs; PPAR target genes and functions in fatty acid metab.; PPARs and control of inflammatory responses; PPARs and atherosclerosis; PPARs and development of the fetal epidermal permeability barrier; and PPARs, carcinogenesis, and control of the cell cycle.

    >> More from SciFinder ^®

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXmvFalsLo%253D&md5=0007e3aa3bab709ad1eb1621d2c6cc38

    
17. 17

    Francque, S.; Verrijken, A.; Caron, S.; Prawitt, J.; Paumelle, R.; Derudas, B.; Lefebvre, P.; Taskinen, M. R.; Van Hul, W.; Mertens, I.; Hubens, G.; Van Marck, E.; Michielsen, P.; Van Gaal, L.; Staels, B. PPARalpha Gene Expression Correlates with Severity and Histological Treatment Response in Patients with Non-Alcoholic Steatohepatitis. J. Hepatol. 2015, 63, 164– 173,  DOI: 10.1016/j.jhep.2015.02.019

    [Crossref], [PubMed], [CAS], Google Scholar

    17

    PPARα gene expression correlates with severity and histological treatment response in patients with non-alcoholic steatohepatitis

    Francque, Sven; Verrijken, An; Caron, Sandrine; Prawitt, Janne; Paumelle, Rejane; Derudas, Bruno; Lefebvre, Philippe; Taskinen, Marja-Riitta; Van Hul, Wim; Mertens, Ilse; Hubens, Guy; Van Marck, Eric; Michielsen, Peter; Van Gaal, Luc; Staels, Bart

    Journal of Hepatology (2015), 63 (1), 164-173CODEN: JOHEEC; ISSN:0168-8278. (Elsevier B.V.)

    Peroxisome proliferator-activated receptors (PPARs) have been implicated in non-alc. steatohepatitis (NASH) pathogenesis, mainly based on animal data. Gene expression data in NASH patients are scarce. We studied liver PPARα, β/δ, and γ expression in a large cohort of obese patients assessed for presence of NAFLD at baseline and 1 yr follow-up. Patients presented to the obesity clinic underwent a hepatic work-up. If NAFLD was suspected, liver biopsy was performed. Gene expression was studied by mRNA quantification. Patients were reassessed after 1 yr.125 patients were consecutively included in the study, of which 85 patients had paired liver biopsy taken at 1 yr of follow-up. Liver PPARα expression neg. correlated with the presence of NASH (p = 0.001) and with severity of steatosis (p = 0.003), ballooning (p = 0.001), NASH activity score (p = 0.008) and fibrosis (p = 0.003). PPARα expression was pos. correlated to adiponectin (R2 = 0.345, p = 0.010) and inversely correlated to visceral fat (R2 = -0.343, p <0.001), HOMA IR (R2 = -0.411, p <0.001) and CK18 (R2 = -0.233, p = 0.012). Liver PPARβ/δ and PPARγ expression did not correlate with any histol. feature nor with glucose metab. or serum lipids. At 1 yr, correlation of PPARα expression with liver histol. was confirmed. In longitudinal anal., an increase in expression of PPARα and its target genes was significantly assocd. with histol. improvement (p = 0.008). Human liver PPARα gene expression neg. correlates with NASH severity, visceral adiposity and insulin resistance and pos. with adiponectin. Histol. improvement is assocd. with an increase in expression of PPARα and its target genes. These data might suggest that PPARα is a potential therapeutic target in NASH.

    >> More from SciFinder ^®

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXmslGiu70%253D&md5=1956e16f4138702004c9d28f75152c18

    
18. 18

    Liss, K. H.; Finck, B. N. PPARs and Nonalcoholic Fatty Liver Disease. Biochimie 2017, 136, 65– 74,  DOI: 10.1016/j.biochi.2016.11.009

    [Crossref], [PubMed], [CAS], Google Scholar

    18

    PPARs and nonalcoholic fatty liver disease

    Liss, Kim H. H.; Finck, Brian N.

    Biochimie (2017), 136 (), 65-74CODEN: BICMBE; ISSN:0300-9084. (Elsevier Masson SAS)

    Nonalcoholic fatty liver disease (NAFLD) encompasses a range of liver pathol. ranging from simple steatosis to varying degrees of inflammation, hepatocyte injury and fibrosis. Without intervention it can progress to end-stage liver disease and hepatocellular carcinoma. Given its close assocn. with obesity, the prevalence of NAFLD has increased dramatically worldwide. Currently, there are no FDA-approved medications for the treatment of NAFLD and although lifestyle modifications with appropriate diet and exercise have been shown to be beneficial, this has been difficult to achieve and sustain for the majority of patients. As such, the search for effective therapeutic agents is an active area of research. Peroxisome proliferator-activated receptors (PPARs) belong to a class of nuclear receptors. Because of their key role in the transcriptional regulation of mediators of glucose and lipid metab., PPAR ligands have been investigated as possible therapeutic agents. Here we review the current evidence from preclin. and clin. studies investigating the therapeutic potential of PPAR ligands for the treatment of NAFLD.

    >> More from SciFinder ^®

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XitVOltLzF&md5=0f1ce45dd197f8b7f3f1c2b1b8471bcf

    
19. 19

    Tanaka, T.; Yamamoto, J.; Iwasaki, S.; Asaba, H.; Hamura, H.; Ikeda, Y.; Watanabe, M.; Magoori, K.; Ioka, R. X.; Tachibana, K.; Watanabe, Y.; Uchiyama, Y.; Sumi, K.; Iguchi, H.; Ito, S.; Doi, T.; Hamakubo, T.; Naito, M.; Auwerx, J.; Yanagisawa, M.; Kodama, T.; Sakai, J. Activation of Peroxisome Proliferator-Activated Receptor Delta Induces Fatty Acid Beta-Oxidation in Skeletal Muscle and Attenuates Metabolic Syndrome. Proc. Natl. Acad. Sci. U. S. A. 2003, 100, 15924– 15929,  DOI: 10.1073/pnas.0306981100

    [Crossref], [PubMed], [CAS], Google Scholar

    19

    Activation of peroxisome proliferator-activated receptor δ induces fatty acid β-oxidation in skeletal muscle and attenuates metabolic syndrome

    Tanaka, Toshiya; Yamamoto, Joji; Iwasaki, Satoshi; Asaba, Hiroshi; Hamura, Hiroki; Ikeda, Yukio; Watanabe, Mitsuhiro; Magoori, Kenta; Ioka, Ryoichi X.; Tachibana, Keisuke; Watanabe, Yuichiro; Uchiyama, Yasutoshi; Sumi, Koichi; Iguchi, Haruhisa; Ito, Sadayoshi; Doi, Takefumi; Hamakubo, Takao; Naito, Makoto; Auwerx, Johan; Yanagisawa, Masashi; Kodama, Tatsuhiko; Sakai, Juro

    Proceedings of the National Academy of Sciences of the United States of America (2003), 100 (26), 15924-15929CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)

    In this study, we defined the role of peroxisome proliferator-activated receptor β/δ (PPARδ) in metabolic homeostasis by using subtype selective agonists. Anal. of rat L6 myotubes treated with the PPARδ subtype-selective agonist, GW501516, by the Affymetrix oligonucleotide microarrays revealed that PPARδ controls fatty acid oxidn. by regulating genes involved in fatty acid transport, β-oxidn., and mitochondrial respiration. Similar PPARδ-mediated gene activation was obsd. in the skeletal muscle of GW501516-treated mice. Accordingly, GW501516 treatment induced fatty acid β-oxidn. in L6 myotubes as well as in mouse skeletal muscles. Administration of GW501516 to mice fed a high-fat diet ameliorated diet-induced obesity and insulin resistance, an effect accompanied by enhanced metabolic rate and fatty acid β-oxidn., proliferation of mitochondria, and a marked redn. of lipid droplets in skeletal muscles. Despite a modest body wt. change relative to vehicle-treated mice, GW501516 treatment also markedly improved diabetes as revealed by the decrease in plasma glucose and blood insulin levels in genetically obese ob/ob mice. These data suggest that PPARδ is pivotal to control the program for fatty acid oxidn. in the skeletal muscle, thereby ameliorating obesity and insulin resistance through its activation in obese animals.

    >> More from SciFinder ^®

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXhtVCkug%253D%253D&md5=9472c2e5e38e5ec5eff20223cab7c1a2

    
20. 20

    Sprecher, D. L.; Massien, C.; Pearce, G.; Billin, A. N.; Perlstein, I.; Willson, T. M.; Hassall, D. G.; Ancellin, N.; Patterson, S. D.; Lobe, D. C.; Johnson, T. G. Triglyceride:High-Density Lipoprotein Cholesterol Effects in Healthy Subjects Administered a Peroxisome Proliferator Activated Receptor Delta Agonist. Arterioscler., Thromb., Vasc. Biol. 2007, 27, 359– 365,  DOI: 10.1161/01.ATV.0000252790.70572.0c

    [Crossref], [PubMed], [CAS], Google Scholar

    20

    Triglyceride:high-density lipoprotein cholesterol effects in healthy subjects administered a peroxisome proliferator activated receptor δ agonist

    Sprecher, Dennis L.; Massien, Christine; Pearce, Greg; Billin, Andrew N.; Perlstein, Itay; Willson, Timothy M.; Hassall, David G.; Ancellin, Nicolas; Patterson, Scott D.; Lobe, David C.; Johnson, Tony G.

    Arteriosclerosis, Thrombosis, and Vascular Biology (2007), 27 (2), 359-365CODEN: ATVBFA; ISSN:1079-5642. (Lippincott Williams & Wilkins)

    Exercise increases fatty acid oxidn. (FAO), improves blood serum high d. lipoprotein cholesterol (HDLc) and triglycerides (TG), and upregulates skeletal muscle peroxisome proliferator activated receptor (PPAR)δ expression. In parallel, PPARδ agonist-upregulated FAO would induce fatty-acid uptake (via peripheral lipolysis), and influence HDLc and TG-rich lipoprotein particle metab., as suggested in preclin. models. Healthy volunteers were allocated placebo (n = 6) or PPARδ agonist (GW501516) at 2.5 mg (n = 9) or 10 mg (n = 9), orally, once-daily for 2 wk while hospitalized and sedentary. Std. lipid/lipoproteins were measured and in vivo fat feeding studies were conducted. Human skeletal muscle cells were treated with GW501516 in vitro and evaluated for lipid-related gene expression and FAO. Serum TG trended downwards (10 mg), whereas TG clearance post fat-feeding improved with drug. HDLc was enhanced in both treatment groups when compared with the decrease in the placebo group (-11.5%). These findings complimented in vitro cell culture results whereby GW501516 induced FAO and upregulated CPT1 and CD36 expression, in addn. to a 2-fold increase in ABCA1. However, LpL expression remained unchanged. This is the 1st report of a PPARδ agonist administered to man. In this small study, GW501516 significantly influenced HDLc and TGs in healthy volunteers. Enhanced in vivo serum fat clearance, and the 1st demonstrated in vitro upregulation in human skeletal muscle fat utilization and ABCA1 expression, suggests peripheral fat utilization and lipidation as potential mechanisms toward these HDL:TG effects.

    >> More from SciFinder ^®

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXjvFGruw%253D%253D&md5=7d280853bb767e5a0c9ac2f693c2f9d8

    
21. 21

    Adhikary, T.; Wortmann, A.; Schumann, T.; Finkernagel, F.; Lieber, S.; Roth, K.; Toth, P. M.; Diederich, W. E.; Nist, A.; Stiewe, T.; Kleinesudeik, L.; Reinartz, S.; Muller-Brusselbach, S.; Muller, R. The Transcriptional PPARbeta/delta Network in Human Macrophages Defines a Unique Agonist-Induced Activation State. Nucleic Acids Res. 2015, 43, 5033– 5051,  DOI: 10.1093/nar/gkv331

    [Crossref], [PubMed], [CAS], Google Scholar

    21

    The transcriptional PPARβ/δ network in human macrophages defines a unique agonist-induced activation state

    Adhikary, Till; Wortmann, Annika; Schumann, Tim; Finkernagel, Florian; Lieber, Sonja; Roth, Katrin; Toth, Philipp M.; Diederich, Wibke E.; Nist, Andrea; Stiewe, Thorsten; Kleinesudeik, Lara; Reinartz, Silke; Mueller-Bruesselbach, Sabine; Mueller, Rolf

    Nucleic Acids Research (2015), 43 (10), 5033-5051CODEN: NARHAD; ISSN:0305-1048. (Oxford University Press)

    Peroxisome proliferator-activated receptor β/δ (PPARβ/δ) is a lipid ligand-inducible transcription factor with established metabolic functions, whereas its anti-inflammatory function is poorly understood. To address this issue, the authors detd. the global PPARβ/δ-regulated signaling network in human monocyte-derived macrophages. Besides cell type-independent, canonical target genes with metabolic and immune regulatory functions the authors identified a large no. of inflammation-assocd. NFκB and STAT1 target genes that are repressed by agonists. Accordingly, PPARβ/δ agonists inhibited the expression of multiple pro-inflammatory mediators and induced an anti-inflammatory, IL-4-like morphol. phenotype. Surprisingly, bioinformatic analyses also identified immune stimulatory effects. Consistent with this prediction, PPARβ/δ agonists enhanced macrophage survival under hypoxic stress and stimulated CD8+ T cell activation, concomitantly with the repression of immune suppressive target genes and their encoded products CD274 (PD-1 ligand), CD32B (inhibitory Fcγ receptor IIB) and indoleamine 2,3-dioxygenase 1 (IDO-1), as well as a diminished release of the immune suppressive IDO-1 metabolite kynurenine. Comparison with published data revealed a significant overlap of the PPARβ/δ transcriptome with coexpression modules characteristic of both anti-inflammatory and pro-inflammatory cytokines. The authors' findings indicate that PPARβ/δ agonists induce a unique macrophage activation state with strong anti-inflammatory but also specific immune stimulatory components, pointing to a context-dependent function of PPARβ/δ in immune regulation.

    >> More from SciFinder ^®

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsFaitL7O&md5=99573af25eeef717df105cb4bac5185a

    
22. 22

    Hellemans, K.; Michalik, L.; Dittie, A.; Knorr, A.; Rombouts, K.; De Jong, J.; Heirman, C.; Quartier, E.; Schuit, F.; Wahli, W.; Geerts, A. Peroxisome Proliferator-Activated Receptor-Beta Signaling Contributes to Enhanced Proliferation of Hepatic Stellate Cells. Gastroenterology 2003, 124, 184– 201,  DOI: 10.1053/gast.2003.50015

    [Crossref], [PubMed], [CAS], Google Scholar

    22

    Peroxisome proliferator-activated receptor-β signaling contributes to enhanced proliferation of hepatic stellate cells

    Hellemans, Karine; Michalik, Liliane; Dittie, Andrea; Knorr, Andreas; Rombouts, Krista; De Jong, Jan; Heirman, Carlo; Quartier, Erik; Schuit, Frans; Wahli, Walter; Geerts, Albert

    Gastroenterology (2003), 124 (1), 184-201CODEN: GASTAB; ISSN:0016-5085. (W. B. Saunders Co.)

    The peroxisome proliferator-activated nuclear receptors (PPAR-α, PPAR-β, and PPAR-γ), which modulate the expression of genes involved in energy homeostasis, cell cycle, and immune function, may play a role in hepatic stellate cell activation. Previous studies focused on the decreased expression of PPAR-γ in hepatic stellate cell activation but did not investigate the expression and role of the PPAR-α and -β isotypes. The aim of this study was to evaluate the expression of the different PPARs during hepatic stellate cell activation in vitro and in situ and to analyze possible factors that might contribute to their expression. In a second part of the study, the effect of a PPAR-β agonist on acute liver injury was evaluated. The effects of PPAR isotype-specific ligands on hepatic stellate cell transition were evaluated by bromodeoxyuridine incorporation, gel shifts, immunopptn., and use of antisense PPAR-β RNA-expressing adenoviruses. Tumor necrosis factor α-induced PPAR-β phosphorylation and expression was evaluated by metabolic labeling and by using specific P38 inhibitors. Hepatic stellate cells constitutively express high levels of PPAR-β, which become further induced during culture activation and in vivo fibrogenesis. No significant expression of PPAR-α or -γ was found. Stimulation of the P38 mitogen-activated protein kinase pathway modulated the expression of PPAR-β. Transcriptional activation of PPAR-β by L165041 enhanced hepatic stellate cell proliferation. Treatment of rats with a single bolus of CCl4 in combination with L165041 further enhanced the expression of fibrotic markers. PPAR-β is an important signal-transducing factor contributing to hepatic stellate cell proliferation during acute and chronic liver inflammation.

    >> More from SciFinder ^®

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXot1amsQ%253D%253D&md5=27b8900156d13b15c9a368f369c79d73

    
23. 23

    Yu, S.; Matsusue, K.; Kashireddy, P.; Cao, W. Q.; Yeldandi, V.; Yeldandi, A. V.; Rao, M. S.; Gonzalez, F. J.; Reddy, J. K. Adipocyte-Specific Gene Expression and Adipogenic Steatosis in the Mouse Liver Due to Peroxisome Proliferator-Activated Receptor Gamma1 (PPARgamma1) Overexpression. J. Biol. Chem. 2003, 278, 498– 505,  DOI: 10.1074/jbc.M210062200

    [Crossref], [PubMed], [CAS], Google Scholar

    23

    Adipocyte-specific Gene Expression and Adipogenic Steatosis in the Mouse Liver Due to Peroxisome Proliferator-activated Receptor γ1 (PPARγ1) Overexpression

    Yu, Songtao; Matsusue, Kimihiko; Kashireddy, Papreddy; Cao, Wen-Qing; Yeldandi, Vaishalee; Yeldandi, Anjana V.; Rao, M. Sambasiva; Gonzalez, Frank J.; Reddy, Janardan K.

    Journal of Biological Chemistry (2003), 278 (1), 498-505CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)

    Peroxisome proliferator activated-receptor (PPAR) isoforms, α and γ, function as important coregulators of energy (lipid) homeostasis. PPARα regulates fatty acid oxidn. primarily in liver and to a lesser extent in adipose tissue, whereas PPARγ serves as a key regulator of adipocyte differentiation and lipid storage. Of the two PPARγ isoforms, PPARγ1 and PPARγ2 generated by alternative splicing, PPARγ1 isoform is expressed in liver and other tissues, whereas PPARγ2 isoform is expressed exclusively in adipose tissue where it regulates adipogenesis and lipogenesis. Since the function of PPARγ1 in liver is not clear, we have, in this study, investigated the biol. impact of overexpression of PPARγ1 in mouse liver. Adenovirus-PPARγ1 injected into the tail vein induced hepatic steatosis in PPARα-/- mice. Northern blotting and gene expression profiling results showed that adipocyte-specific genes and lipogenesis-related genes are highly induced in PPARα-/- livers with PPARγ1 overexpression. These include adipsin, adiponectin, aP2, caveolin-1, fasting-induced adipose factor, fat-specific gene 27 (FSP27), CD36, Δ9 desaturase, and malic enzyme among others, implying adipogenic transformation of hepatocytes. Of interest is that hepatic steatosis per se, induced either by feeding a diet deficient in choline or developing in fasted PPARα-/- mice, failed to induce the expression of these PPARγ-regulated adipogenesis-related genes in steatotic liver. These results suggest that a high level of PPARγ in mouse liver is sufficient for the induction of adipogenic transformation of hepatocytes with adipose tissue-specific gene expression and lipid accumulation. We conclude that excess PPARγ activity can lead to the development of a novel type of adipogenic hepatic steatosis.

    >> More from SciFinder ^®

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XpvVWgu7g%253D&md5=f8c680a566b67621b7f662861fb14783

    
24. 24

    Ayiomamitis, A. The Epidemiology of Malignant Neoplasia of the Larynx in Canada: 1931–1984. Clin. Otolaryngol. Allied Sci. 1989, 14, 349– 355,  DOI: 10.1111/j.1365-2273.1989.tb00383.x

    [Crossref], [PubMed], [CAS], Google Scholar

    24

    The epidemiology of malignant neoplasia of the larynx in Canada: 1931-1984

    Ayiomamitis A

    Clinical otolaryngology and allied sciences (1989), 14 (4), 349-55 ISSN:0307-7772.

    Canadian patterns of morbidity and mortality from laryngeal carcinoma were examined for the periods 1970-1980 and 1931-1984, respectively. Age-standardized morbidity rates had risen significantly in both males and females (P = 0.0001 and 0.0116) during 1970-1980 with rates for males increasing by more than 0.28 additional cases per 100,000 population per year since 1970. Analysis of age-specific rates over time indicates that the rise in standardized rates is attributable to significant increases in rates for males aged 45-54, 55-64 and 65-74 (P less than 0.006) and females aged 45-54, 55-64, and 75-84 (P less than 0.045). Rates for males aged 55-64 demonstrated the most dramatic rate of change of any age group at over 1.8 additional new cases per 100,000 population per year since 1970. Analysis of age-standardized mortality rates reveals that rates for males have risen significantly during the period 1931-1984 whereas rates for females have declined significantly (P = 0.0001 and 0.005, respectively). The rise in age-standardized mortality rates for males is associated with corresponding significant rates of increase in age-specific rates for males aged 45-54, 55-64, 65-74, 75-84 and 85 + (P less than 0.02) whereas the decline in rates for females is associated with significant declines in rates for women aged 35-44, 45-54, and 75-84 (P less than 0.05). Males aged 75-84 had the greatest rate of change at 0.20 additional new deaths per 100,000 population per year since 1931.

    >> More from SciFinder ^®

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK3c%252FjtV2lsA%253D%253D&md5=e83809cc402dd90d1f8faa86ac1aa792

    
25. 25

    Brown, P. J.; Winegar, D. A.; Plunket, K. D.; Moore, L. B.; Lewis, M. C.; Wilson, J. G.; Sundseth, S. S.; Koble, C. S.; Wu, Z.; Chapman, J. M.; Lehmann, J. M.; Kliewer, S. A.; Willson, T. M. A Ureido-Thioisobutyric Acid (GW9578) is a Subtype-Selective PPARalpha Agonist with Potent Lipid-Lowering Activity. J. Med. Chem. 1999, 42, 3785– 3788,  DOI: 10.1021/jm9903601

    [ACS Full Text ], [CAS], Google Scholar

    25

    A Ureido-Thioisobutyric Acid (GW9578) Is a Subtype-Selective PPARα Agonist with Potent Lipid-Lowering Activity

    Brown, Peter J.; Winegar, Deborah A.; Plunket, Kelli D.; Moore, Linda B.; Lewis, Michael C.; Wilson, Joan G.; Sundseth, Scott S.; Koble, Cecilia S.; Wu, Zhengdong; Chapman, James M.; Lehmann, Juergen M.; Kliewer, Steven A.; Willson, Timothy M.

    Journal of Medicinal Chemistry (1999), 42 (19), 3785-3788CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

    Several fibrates and ureido-fibrates were compared for their agonist activity at the PPARα (peroxisome proliferator-activated receptor-α). The ureido-fibrates were potent agonists at murine PPARα:, however, like the fibrates, they showed only moderate levels of subtype selectivity. The ureido-thioisobutyric acid deriv. (GW9578) was prepd. and shown to be a selective PPARα agonist. The lipid-lowering activity of the fibrates and GW9578 were detd.: GW9578 had good activity. The lipid-lowering activity of the fibrates was correlated with their lipid-lowering activity. GW9578 decreased total LDL cholesterol and apoC-III levels, indicating that its mechanism was clin. relevant.

    >> More from SciFinder ^®

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXls1Ojsrg%253D&md5=c24192af1dc60069fb403816850b8c57

    
26. 26

    Fernandez-Miranda, C.; Perez-Carreras, M.; Colina, F.; Lopez-Alonso, G.; Vargas, C.; Solis-Herruzo, J. A. A Pilot Trial of Fenofibrate for the Treatment of Non-Alcoholic Fatty Liver Disease. Dig. Liver Dis. 2008, 40, 200– 205,  DOI: 10.1016/j.dld.2007.10.002

    [Crossref], [PubMed], [CAS], Google Scholar

    26

    A pilot trial of fenofibrate for the treatment of non-alcoholic fatty liver disease

    Fernandez-Miranda, C.; Perez-Carreras, M.; Colina, F.; Lopez-Alonso, G.; Vargas, C.; Solis-Herruzo, J. A.

    Digestive and Liver Disease (2008), 40 (3), 200-205CODEN: DLDIFK; ISSN:1590-8658. (Elsevier B.V.)

    Background: Dyslipidemia and insulin resistance are two important risk factors for non-alc. fatty liver disease. Both factors can improve with fenofibrate. Aims: To evaluate the effect of fenofibrate on the clin., anal. and histol. evolution of patients with non-alc. fatty liver disease. Subjects and methods: Sixteen consecutive patients with biopsy-confirmed non-alc. fatty liver disease were treated with 200 mg/day of fenofibrate for 48 wk. A clin. and biochem. follow-up was done every 3 mo. A new liver biopsy was performed in all patients at the end of therapy. Results: All patients completed 48 wk of therapy with fenofibrate, without adverse events. At the end of the study, a significant decrease in triglyceride, glucose, alk. phosphatase and gamma-glutamyl transpeptidase and an increase of apolipoprotein A1 levels were found. Insulin levels and insulin resistance showed a trend to decrease. Moreover, a redn. in the proportion of patients with abnormal aminotransferase levels (>45IU/L) was obsd. (alanine aminotransferase: 93.7% vs. 62.5%, p = 0.02; aspartate aminotransferase: 50% vs. 18.7%, p = 0.02). The body mass index did not show any significant change, but the proportion of patients with metabolic syndrome decreased significantly (43.7% vs. 18.7%, p = 0.04). A control biopsy after treatment revealed a decrease in the grade of hepatocellular ballooning degeneration (p = 0.03), but the grade of steatosis, lobular inflammation, fibrosis or non-alc. fatty liver disease activity score did not change significantly. Conclusions: In patients with non-alc. fatty liver disease, treatment with fenofibrate is safe and improves metabolic syndrome, glucose and liver tests. However, its effects on liver histol. are minimal.

    >> More from SciFinder ^®

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXltFaisr8%253D&md5=6a1f2748bd06e51a27dbb31ee0a2995f

    
27. 27

    Sanyal, A. J.; Chalasani, N.; Kowdley, K. V.; McCullough, A.; Diehl, A. M.; Bass, N. M.; Neuschwander-Tetri, B. A.; Lavine, J. E.; Tonascia, J.; Unalp, A.; Van Natta, M.; Clark, J.; Brunt, E. M.; Kleiner, D. E.; Hoofnagle, J. H.; Robuck, P. R.; NASH CRN Pioglitazone, Vitamin E, or Placebo for Nonalcoholic Steatohepatitis. N. Engl. J. Med. 2010, 362, 1675– 1685,  DOI: 10.1056/NEJMoa0907929

    [Crossref], [PubMed], [CAS], Google Scholar

    27

    Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis

    Sanyal, Arun J.; Chalasani, Naga; Kowdley, Kris V.; McCullough, Arthur; Diehi, Anna Mae; Bass, Nathan M.; Neuschwander-Tetri, Brent A.; Lavine, Joel E.; Tonascia, James; Unalp, Aynur; Van Natta, Mark; Clark, Jeanne; Brunt, Elizabeth M.; Kleiner, David E.; Hoofnagle, Jay H.; Robuck, Patricia R.

    New England Journal of Medicine (2010), 362 (18), 1675-1685CODEN: NEJMAG; ISSN:0028-4793. (Massachusetts Medical Society)

    Background: Nonalcoholic steatohepatitis is a common liver disease that can progress to cirrhosis. Currently, there is no established treatment for this disease. Methods: We randomly assigned 247 adults with nonalcoholic steatohepatitis and without diabetes to receive pioglitazone at a dose of 30 mg daily (80 subjects), vitamin E at a dose of 800 IU daily (84 subjects), or placebo (83 subjects), for 96 wk. The primary outcome was an improvement in histol. features of nonalcoholic steatohepatitis, as assessed with the use of a composite of standardized scores for steatosis, lobular inflammation, hepatocellular ballooning, and fibrosis. Given the two planned primary comparisons, P values of less than 0.025 were considered to indicate statistical significance. Results: Vitamin E therapy, as compared with placebo, was assocd. with a significantly higher rate of improvement in nonalcoholic steatohepatitis (43% vs. 19%, P = 0.001), but the difference in the rate of improvement with pioglitazone as compared with placebo was not significant (34% and 19%, resp.; P = 0.04). Serum alanine and aspartate aminotransferase levels were reduced with vitamin E and with pioglitazone, as compared with placebo (P < 0.001 for both comparisons), and both agents were assocd. with redns. in hepatic steatosis (P = 0.005 for vitamin E and P < 0.001 for pioglitazone) and lobular inflammation (P = 0.02 for vitamin E and P = 0.004 for pioglitazone) but not with improvement in fibrosis scores (P = 0.24 for vitamin E and P = 0.12 for pioglitazone). Subjects who received pioglitazone gained more wt. than did those who received vitamin E or placebo; the rates of other side effects were similar among the three groups. Conclusions: Vitamin E was superior to placebo for the treatment of nonalcoholic steatohepatitis in adults without diabetes. There was no benefit of pioglitazone over placebo for the primary outcome; however, significant benefits of pioglitazone were obsd. for some of the secondary outcomes.

    >> More from SciFinder ^®

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXls1Oltr4%253D&md5=f439009e1d05196c7a9f94ca7cbc11cb

    
28. 28

    Willson, T. M.; Cobb, J. E.; Cowan, D. J.; Wiethe, R. W.; Correa, I. D.; Prakash, S. R.; Beck, K. D.; Moore, L. B.; Kliewer, S. A.; Lehmann, J. M. The Structure-Activity Relationship Between Peroxisome Proliferator-Activated Receptor Gamma Agonism and the Antihyperglycemic Activity of Thiazolidinediones. J. Med. Chem. 1996, 39, 665– 668,  DOI: 10.1021/jm950395a

    [ACS Full Text ], [CAS], Google Scholar

    28

    The Structure-Activity Relationship between Peroxisome Proliferator-Activated Receptor γ Agonism and the Anti-Hyperglycemic Activity of Thiazolidinediones

    Willson, Timothy M.; Cobb, Jeffrey E.; Cowan, David J.; Wiethe, Robert W.; Correa, Itzela D.; Prakash, Shimoga R.; Beck, Kelli D.; Moore, Linda B.; Kliewer, Steven A.; Lehmann, Juergen M.

    Journal of Medicinal Chemistry (1996), 39 (3), 665-8CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

    A series of thiazolidinediones and related compds. with known antidiabetic activity were tested for their in vitro activity on the peroxisome proliferator-activated receptor γ (PPARγ). A correlation between the PPARγ agonist activity and the in vivo antihyperglycemic potency in ob/ob mice was obsd. These results suggest that PPARγ is the mol. target for the antidiabetic activity of the thiazolidinediones.

    >> More from SciFinder ^®

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28Xjt1Ortw%253D%253D&md5=cc73c6a8157b6ea258b2f6b3deb6c817

    
29. 29

    Sauerberg, P.; Pettersson, I.; Jeppesen, L.; Bury, P. S.; Mogensen, J. P.; Wassermann, K.; Brand, C. L.; Sturis, J.; Woldike, H. F.; Fleckner, J.; Andersen, A. S.; Mortensen, S. B.; Svensson, L. A.; Rasmussen, H. B.; Lehmann, S. V.; Polivka, Z.; Sindelar, K.; Panajotova, V.; Ynddal, L.; Wulff, E. M. Novel Tricyclic-Alpha-Alkyloxyphenylpropionic Acids: Dual PPARalpha/gamma Agonists with Hypolipidemic and Antidiabetic Activity. J. Med. Chem. 2002, 45, 789– 804,  DOI: 10.1021/jm010964g

    [ACS Full Text ], [CAS], Google Scholar

    29

    Novel Tricyclic-α-alkyloxyphenylpropionic Acids: Dual PPARα/γ Agonists with Hypolipidemic and Antidiabetic Activity

    Sauerberg, Per; Pettersson, Ingrid; Jeppesen, Lone; Bury, Paul S.; Mogensen, John P.; Wassermann, Karsten; Brand, Christian L.; Sturis, Jeppe; Woeldike, Helle F.; Fleckner, Jan; Andersen, Anne-Sofie T.; Mortensen, Steen B.; Svensson, L. Anders; Rasmussen, Hanne B.; Lehmann, Soren V.; Polivka, Zdenek; Sindelar, Karel; Panajotova, Vladimira; Ynddal, Lars; Wulff, Erik M.

    Journal of Medicinal Chemistry (2002), 45 (4), 789-804CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

    Tricyclic α-ethoxy phenylpropionic acid derivs. such as nonracemic carbazoleethoxypropionic acid I were prepd. and tested for their PPARα and PPARγ agonist activities as potential antihyperlipidemic and antidiabetic agents. Mol. mechanics and X-ray crystallog. data of the complex of the PPARγ receptor with I were obtained. Db/db mice treated with I showed improved insulin sensitivity over treatment with either pioglitazone or rosiglitazone, suggesting in vivo PPARγ activity. Rats fed a high-cholesterol diet and treated with I also showed decreased plasma triglycerides and cholesterol after 4 days treatment, indicating in vivo PPARα activity. Pharmacokinetics of selected compds. suggested that extended drug exposure improved the in vivo activity of in vitro active compds.

    >> More from SciFinder ^®

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XlvFSitA%253D%253D&md5=0d196b2c1e89d51a5195a249585e352e

    
30. 30

    Dormandy, J.; Bhattacharya, M.; van Troostenburg de Bruyn, A. R.; PROactive Investigators Safety and Tolerability of Pioglitazone in High-Risk Patients with Type 2 Diabetes: An Overview of Data from PROactive. Drug Saf. 2009, 32, 187– 202,  DOI: 10.2165/00002018-200932030-00002

    [Crossref], [PubMed], [CAS], Google Scholar

    30

    Safety and tolerability of pioglitazone in high-risk patients with type 2 diabetes an overview of data from PROactive

    Dormandy, John; Bhattacharya, Mondira; van Troostenburg de Bruyn, Anne-Ruth

    Drug Safety (2009), 32 (3), 187-202CODEN: DRSAEA; ISSN:0114-5916. (Wolters Kluwer Health)

    A review. People with type 2 diabetes mellitus have an excess risk of macrovascular disease and a poorer prognosis. PROactive (PROspective pioglitazone Clin. Trial In macrovascular Events) was a landmark study of secondary cardiovascular disease (CVD) prevention in type 2 diabetes that suggested a beneficial effect of pioglitazone therapy on macrovascular outcomes. Previous studies have already shown that pioglitazone has a good safety and tolerability profile in people with type 2 diabetes, but PROactive provided an opportunity to assess tolerability and safety assocd. with long-term exposure in a vulnerable subpopulation at very high cardiovascular risk. This review discusses all the key safety and tolerability characteristics assocd. with pioglitazone therapy in PROactive. As in previous studies, pioglitazone was assocd. with typical, but manageable, increases in edema (26.4% vs 15.1% for placebo) and wt. gain (mean change of +3.8 kg vs -0.6 kg for placebo). Increased hypoglycemia with pioglitazone was consistent with improved glycemic control. Despite more reports of serious heart failure in the pioglitazone group (5.7% vs 4.1% for placebo), there was a proportional improvement in macrovascular outcomes among patients developing heart failure, and abs. rates of macrovascular events and mortality were similar to those in the placebo group. Liver function tests confirmed the hepatic safety of pioglitazone with long-term use and revealed a tendency to improved hepatic function, which may reflect redns. in liver fat. The comparative incidence of malignancies was similar; however, more cases of bladder neoplasm (14 vs 5) and fewer cases of breast cancer (3 vs 11) were obsd. in the pioglitazone vs. placebo arms of the study. A higher rate of bone fractures obsd. among pioglitazone treated female patients (5.1% vs 2.5%) warrants further investigation. Overall, safety and tolerability was predictable, and adverse events were not treatment limiting. These results suggest that any beneficial effects of pioglitazone on macrovascular outcomes are accompanied by good long-term tolerability in this population of very high-risk patients with type 2 diabetes and established CVD.

    >> More from SciFinder ^®

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXlvFCmu7s%253D&md5=26f2a5eb54b4cf7de0311da5cbe71d7d

    
31. 31

    Bays, H. E.; Schwartz, S.; Littlejohn, T., III; Kerzner, B.; Krauss, R. M.; Karpf, D. B.; Choi, Y. J.; Wang, X.; Naim, S.; Roberts, B. K. MBX-8025, a Novel Peroxisome Proliferator Receptor-Delta Agonist: Lipid and Other Metabolic Effects in Dyslipidemic Overweight Patients Treated with and without Atorvastatin. J. Clin. Endocrinol. Metab. 2011, 96, 2889– 2897,  DOI: 10.1210/jc.2011-1061

    [Crossref], [PubMed], [CAS], Google Scholar

    31

    MBX-8025, a novel peroxisome proliferator receptor-δ agonist: lipid and other metabolic effects in dyslipidemic overweight patients treated with and without atorvastatin

    Bays, Harold E.; Schwartz, Sherwyn; Littlejohn, Thomas, III; Kerzner, Boris; Krauss, Ronald M.; Karpf, David B.; Choi, Yun-Jung; Wang, Xueyan; Naim, Sue; Roberts, Brian K.

    Journal of Clinical Endocrinology and Metabolism (2011), 96 (9), 2889-2897CODEN: JCEMAZ; ISSN:0021-972X. (Endocrine Society)

    Context: Preclin. and clin. studies suggest that peroxisome proliferator-activated receptor (PPAR)-δ agonists favorably affect multiple metabolic parameters that are otherwise proatherogenic, many that are not optimally managed with statins alone. Objective: The aim of this study was to evaluate the effects of MBX-8025 (a novel PPAR-δ agonist) on lipid and other metabolic parameters assocd. with increased atherosclerotic risk, administered alone and in combination with atorvastatin. Design and Setting: This was a randomized, double-blind, placebo-controlled, parallel group proof-of-concept study conducted at 30 U.S. research sites. Participants: This study evaluated 181 overweight men and women with mixed dyslipidemia. Intervention(s): Subjects were administered once daily placebo, atorvastatin 20 mg, or MBX-8025 at 50 or 100 mg alone or combined with atorvastatin for 8 wk. Main Outcome Measures: The main efficacy measures included change from baseline in apolipoprotein B-100, lipid levels, high-sensitivity C-reactive protein, and addnl. metabolic parameters, as well as the effect on the metabolic syndrome and LDL particle size. Results: Compared to placebo, MBX-8025 alone and in combination with atorvastatin significantly (P < 0.05) reduced apolipoprotein B-100 20-38%, LDL 18-43%, triglycerides 26-30%, non-high-d. lipoprotein cholesterol 18-41%, free fatty acids 16-28%, and high-sensitivity C-reactive protein 43-72%; it raised high-d. lipoprotein cholesterol 1-12% and also reduced the no. of patients with the metabolic syndrome and a preponderance of small LDL particles. MBX-8025 was safe and generally well-tolerated. MBX-8025 also reduced liver enzyme levels. Conclusion: MBX-8025, a novel PPAR-δ agonist, favorably affected multiple metabolic parameters with and without atorvastatin. A more complete understanding of MBX-8025 requires a larger future study.

    >> More from SciFinder ^®

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXht1SktLzE&md5=3e46c42efb64ace0ee4090af910cc07f

    
32. 32

    Zhang, R.; Wang, A.; DeAngelis, A.; Pelton, P.; Xu, J.; Zhu, P.; Zhou, L.; Demarest, K.; Murray, W. V.; Kuo, G. H. Discovery of Para-Alkylthiophenoxyacetic Acids as a Novel Series of Potent and Selective PPARdelta Agonists. Bioorg. Med. Chem. Lett. 2007, 17, 3855– 3859,  DOI: 10.1016/j.bmcl.2007.05.007

    [Crossref], [PubMed], [CAS], Google Scholar

    32

    Discovery of para-alkylthiophenoxyacetic acids as a novel series of potent and selective PPARδ agonists

    Zhang, Rui; Wang, Aihua; DeAngelis, Alan; Pelton, Patricia; Xu, Jun; Zhu, Peifang; Zhou, Lubing; Demarest, Keith; Murray, William V.; Kuo, Gee-Hong

    Bioorganic & Medicinal Chemistry Letters (2007), 17 (14), 3855-3859CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Ltd.)

    A novel series of potent and selective PPARδ agonists, p-alkylthiophenoxyacetic acids [I, X = S, O, S(O); Y = O, CH2; R = OH, MeO, OMOM, Me, etc.] was identified. The synthesis and structure-activity relationships are described.

    >> More from SciFinder ^®

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXmvVCltbw%253D&md5=b7974387d421bb4f1fa6882ab89733df

    
33. 33

    Cymabay https://ir.cymabay.com/press-releases/detail/476/cymabay-therapeutics-halts-clinical-development-of-seladelpar (accessed Nov 26, 2019).

    Google Scholar

    There is no corresponding record for this reference.

    
34. 34

    Wright, M. B.; Bortolini, M.; Tadayyon, M.; Bopst, M. Minireview: Challenges and Opportunities in Development of PPAR Agonists. Mol. Endocrinol. 2014, 28, 1756– 1768,  DOI: 10.1210/me.2013-1427

    [Crossref], [PubMed], [CAS], Google Scholar

    34

    Minireview: challenges and opportunities in development of PPAR agonists

    Wright, Matthew B.; Bortolini, Michele; Tadayyon, Moh; Bopst, Martin

    Molecular Endocrinology (2014), 28 (11), 1756-1768, 13 pp.CODEN: MOENEN; ISSN:1944-9917. (Endocrine Society)

    A review. The clin. impact of the fibrate and thiazolidinedione drugs on dyslipidemia and diabetes is driven mainly through activation of two transcription factors, peroxisome proliferator-activated receptors (PPAR)-α and PPAR-γ. However, substantial differences exist in the therapeutic and side-effect profiles of specific drugs. This has been attributed primarily to the complexity of drug-target complexes that involve many coregulatory proteins in the context of specific target gene promoters. Recent data have revealed that some PPAR ligands interact with other non-PPAR targets. Here we review concepts used to develop new agents that preferentially modulate transcriptional complex assembly, target more than one PPAR receptor simultaneously, or act as partial agonists. We highlight newly described on-target mechanisms of PPAR regulation including phosphorylation and nongenomic regulation. We briefly describe the recently discovered non-PPAR protein targets of thiazolidinediones, mitoNEET, and mTOT. Finally, we summarize the contributions of on- and off-target actions to select therapeutic and side effects of PPAR ligands including insulin sensitivity, cardiovascular actions, inflammation, and carcinogenicity.

    >> More from SciFinder ^®

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXisFamtbY%253D&md5=9f52aab240185e1adf107feb7aa520a7

    
35. 35

    Ratziu, V.; Harrison, S. A.; Francque, S.; Bedossa, P.; Lehert, P.; Serfaty, L.; Romero-Gomez, M.; Boursier, J.; Abdelmalek, M.; Caldwell, S.; Drenth, J.; Anstee, Q. M.; Hum, D.; Hanf, R.; Roudot, A.; Megnien, S.; Staels, B.; Sanyal, A.; GOLDEN-505 Investigator Study Group Elafibranor, an Agonist of the Peroxisome Proliferator-Activated Receptor-alpha and -delta, Induces Resolution of Nonalcoholic Steatohepatitis without Fibrosis Worsening. Gastroenterology 2016, 150, 1147– 1159,  DOI: 10.1053/j.gastro.2016.01.038

    [Crossref], [PubMed], [CAS], Google Scholar

    35

    Elafibranor, an Agonist of the Peroxisome Proliferator-Activated Receptor-α and -δ, Induces Resolution of Nonalcoholic Steatohepatitis Without Fibrosis Worsening

    Ratziu, Vlad; Harrison, Stephen A.; Francque, Sven; Bedossa, Pierre; Lehert, Philippe; Serfaty, Lawrence; Romero-Gomez, Manuel; Boursier, Jerome; Abdelmalek, Manal; Caldwell, Steve; Drenth, Joost; Anstee, Quentin M.; Hum, Dean; Hanf, Remy; Roudot, Alice; Megnien, Sophie; Staels, Bart; Sanyal, Arun

    Gastroenterology (2016), 150 (5), 1147-1159.e5CODEN: GASTAB; ISSN:0016-5085. (Elsevier)

    Elafibranor is an agonist of the peroxisome proliferator-activated receptor-α and peroxisome proliferator-activated receptor-δ. Elafibranor improves insulin sensitivity, glucose homeostasis, and lipid metab. and reduces inflammation. We assessed the safety and efficacy of elafibranor in an international, randomized, double-blind placebo-controlled trial of patients with nonalcoholic steatohepatitis (NASH). Patients with NASH without cirrhosis were randomly assigned to groups given elafibranor 80 mg (n = 93), elafibranor 120 mg (n = 91), or placebo (n = 92) each day for 52 wk at sites in Europe and the United States. Clin. and lab. evaluations were performed every 2 mo during this 1-yr period. Liver biopsies were then collected and patients were assessed 3 mo later. The primary outcome was resoln. of NASH without fibrosis worsening, using protocol-defined and modified definitions. Data from the groups given the different doses of elafibranor were compared with those from the placebo group using step-down logistic regression, adjusting for baseline nonalcoholic fatty liver disease activity score. In intention-to-treat anal., there was no significant difference between the elafibranor and placebo groups in the protocol-defined primary outcome. However, NASH resolved without fibrosis worsening in a higher proportion of patients in the 120-mg elafibranor group vs the placebo group (19% vs 12%; odds ratio = 2.31; 95% confidence interval: 1.02-5.24; P = .045), based on a post-hoc anal. for the modified definition. In post-hoc analyses of patients with nonalcoholic fatty liver disease activity score ≥4 (n = 234), elafibranor 120 mg resolved NASH in larger proportions of patients than placebo based on the protocol definition (20% vs 11%; odds ratio = 3.16; 95% confidence interval: 1.22-8.13; P = .018) and the modified definitions (19% vs 9%; odds ratio = 3.52; 95% confidence interval: 1.32-9.40; P = .013). Patients with NASH resoln. after receiving elafibranor 120 mg had reduced liver fibrosis stages compared with those without NASH resoln. (mean redn. of 0.65 ± 0.61 in responders for the primary outcome vs an increase of 0.10 ± 0.98 in nonresponders; P < .001). Liver enzymes, lipids, glucose profiles, and markers of systemic inflammation were significantly reduced in the elafibranor 120-mg group vs the placebo group. Elafibranor was well tolerated and did not cause wt. gain or cardiac events, but did produce a mild, reversible increase in serum creatinine (effect size vs placebo: increase of 4.31 ± 1.19 μmol/L; P < .001). A post-hoc anal. of data from trial of patients with NASH showed that elafibranor (120 mg/d for 1 yr) resolved NASH without fibrosis worsening, based on a modified definition, in the intention-to-treat anal. and in patients with moderate or severe NASH. However, the predefined end point was not met in the intention to treat population. Elafibranor was well tolerated and improved patients' cardiometabolic risk profile. ClinicalTrials.gov no.: NCT01694849.

    >> More from SciFinder ^®

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xms1Klu7g%253D&md5=cee5c53be700bd0a9eadb455390a222c

    
36. 36

    Genfit https://www.genfit.com/press-release/genfit-positive-36-month-dsmb-recommendation-for-continuation-of-phase-3-resolve-it-study-of-elafibranor-in-nash/ (accessed Sept 25, 2019).

    Google Scholar

    There is no corresponding record for this reference.

    
37. 37

    Han, C. Y. Update on FXR Biology: Promising Therapeutic Target?. Int. J. Mol. Sci. 2018, 19, 2069,  DOI: 10.3390/ijms19072069

    [Crossref], [CAS], Google Scholar

    37

    Update on FXR biology: promising therapeutic target?

    Han, Chang Yeob

    International Journal of Molecular Sciences (2018), 19 (7), 2069/1-2069/25CODEN: IJMCFK; ISSN:1422-0067. (MDPI AG)

    A review. Farnesoid X receptor (FXR), a metabolic nuclear receptor, plays crit. roles in the maintenance of systemic energy homeostasis and the integrity of many organs, including liver and intestine. It regulates bile acid, lipid, and glucose metab., and contributes to inter-organ communication, in particular the enterohepatic signaling pathway, through bile acids and fibroblast growth factor-15/19 (FGF-15/19). The metabolic effects of FXR are also involved in gut microbiota. In addn., FXR has various functions in the kidney, adipose tissue, pancreas, cardiovascular system, and tumorigenesis. Consequently, the deregulation of FXR may lead to abnormalities of specific organs and metabolic dysfunction, allowing the protein as an attractive therapeutic target for the management of liver and/or metabolic diseases. Indeed, many FXR agonists have been being developed and are under pre-clin. and clin. investigations. Although obeticholic acid (OCA) is one of the promising candidates, significant safety issues have remained. The effects of FXR modulation might be multifaceted according to tissue specificity, disease type, and/or energy status, suggesting the careful use of FXR agonists. This review summarizes the current knowledge of systemic FXR biol. in various organs and the gut-liver axis, particularly regarding the recent advancement in these fields, and also provides pharmacol. aspects of FXR modulation for rational therapeutic strategies and novel drug development.

    >> More from SciFinder ^®

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXisFKltLbL&md5=b2497c742af491002d92b5bf049040ff

    
38. 38

    Kim, I.; Ahn, S. H.; Inagaki, T.; Choi, M.; Ito, S.; Guo, G. L.; Kliewer, S. A.; Gonzalez, F. J. Differential Regulation of Bile Acid Homeostasis by the Farnesoid X Receptor in Liver and Intestine. J. Lipid Res. 2007, 48, 2664– 2672,  DOI: 10.1194/jlr.M700330-JLR200

    [Crossref], [PubMed], [CAS], Google Scholar

    38

    Differential regulation of bile acid homeostasis by the farnesoid X receptor in liver and intestine

    Kim, Insook; Ahn, Sung-Hoon; Inagaki, Takeshi; Choi, Mihwa; Ito, Shinji; Guo, Grace L.; Kliewer, Steven A.; Gonzalez, Frank J.

    Journal of Lipid Research (2007), 48 (12), 2664-2672CODEN: JLPRAW; ISSN:0022-2275. (American Society for Biochemistry and Molecular Biology, Inc.)

    Bile acid concns. are controlled by a feed-back regulatory pathway whereby activation of the farnesoid X receptor (FXR) represses transcription of both the CYP7A1 gene, encoding the rate-limiting enzyme in the classic bile acid synthesis pathway, and the CYP8B1 gene, required for synthesis of cholic acid. The tissue-specific roles of FXR were examd. using liver- and intestine-specific FXR-null models. FXR deficiency in either liver (FxrΔL) or intestine (FxrΔIE) increased bile acid pool size. Treatment with the FXR-selective agonist GW4064 significantly repressed CYP7A1 in FxrΔL mice but not FxrΔIE mice, demonstrating that activation of FXR in intestine but not liver is required for short-term repression of CYP7A1 in liver. This intestinal-specific effect of FXR is likely mediated through induction of the hormone FGF15, which suppresses CYP7A1. In comparison to CYP7A1, FXR-mediated repression of CYP8B1 was more dependent on the presence of FXR in liver and less dependent on its presence in intestine. Consistent with these findings, recombinant FGF15 repressed CYP7A1 mRNA levels without affecting CYP8B1 expression. These data provide evidence that FXR-mediated repression of bile acid synthesis requires the complementary actions of FXR in both liver and intestine and reveal mechanistic differences in feedback repression of CYP7A1 and CYP8B1.

    >> More from SciFinder ^®

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhsValtLzM&md5=d437790779893dd9aa4c47610885d063

    
39. 39

    Chiang, J. Y. Bile Acid Metabolism and Signaling. Compr. Physiol. 2013, 3, 1191– 1212,  DOI: 10.1002/cphy.c120023

    [Crossref], [PubMed], [CAS], Google Scholar

    39

    Bile acid metabolism and signaling

    Chiang John Y L

    Comprehensive Physiology (2013), 3 (3), 1191-212 ISSN:.

    Bile acids are important physiological agents for intestinal nutrient absorption and biliary secretion of lipids, toxic metabolites, and xenobiotics. Bile acids also are signaling molecules and metabolic regulators that activate nuclear receptors and G protein-coupled receptor (GPCR) signaling to regulate hepatic lipid, glucose, and energy homeostasis and maintain metabolic homeostasis. Conversion of cholesterol to bile acids is critical for maintaining cholesterol homeostasis and preventing accumulation of cholesterol, triglycerides, and toxic metabolites, and injury in the liver and other organs. Enterohepatic circulation of bile acids from the liver to intestine and back to the liver plays a central role in nutrient absorption and distribution, and metabolic regulation and homeostasis. This physiological process is regulated by a complex membrane transport system in the liver and intestine regulated by nuclear receptors. Toxic bile acids may cause inflammation, apoptosis, and cell death. On the other hand, bile acid-activated nuclear and GPCR signaling protects against inflammation in liver, intestine, and macrophages. Disorders in bile acid metabolism cause cholestatic liver diseases, dyslipidemia, fatty liver diseases, cardiovascular diseases, and diabetes. Bile acids, bile acid derivatives, and bile acid sequestrants are therapeutic agents for treating chronic liver diseases, obesity, and diabetes in humans.

    >> More from SciFinder ^®

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3sfltFWisw%253D%253D&md5=7ad6bcbb55a8facef4457a0949b9f75c

    
40. 40

    Karasawa, K.; Tanigawa, K.; Harada, A.; Yamashita, A. Transcriptional Regulation of Acyl-CoA:Glycerol-sn-3-Phosphate Acyltransferases. Int. J. Mol. Sci. 2019, 20, 964,  DOI: 10.3390/ijms20040964

    [Crossref], [CAS], Google Scholar

    40

    Transcriptional regulation of Acyl-CoA:Glycerol-sn-3-phosphate acyltransferases

    Karasawa, Ken; Tanigawa, Kazunari; Harada, Ayako; Yamashita, Atsushi

    International Journal of Molecular Sciences (2019), 20 (4), 964CODEN: IJMCFK; ISSN:1422-0067. (MDPI AG)

    A review. Acyl-CoA:glycerol-sn-3-phosphate acyltransferase (GPAT) is an enzyme responsible for the rate-limiting step in the synthesis of glycerophospholipids and triacylglycerol (TAG). The enzymes of mammalian species are classified into four isoforms; GPAT1 and GPAT2 are localized in the mitochondrial outer membrane, whereas GPAT3 and GPAT4 are localized in the endoplasmic reticulum membrane. The activity of each enzyme expressed is assocd. with physiol. and pathol. functions. The transcriptional regulation is well known, particularly in GPAT1. GPAT1 mRNA expression is mainly regulated by the binding of the transcriptional factor SREBP-1c to the specific element (the sterol regulatory element) flanking the GPAT1 promoter. The TAG level is controlled by the insulin-induced transcriptional expression of GPAT1, which occupies most of the GPAT activity in the liver. The transcriptional regulation of the other three GPAT isoforms remains undetd. in detail. It is predicted that retinoic acid serves as a transcription factor in the GPAT2 promoter. PPARγ (peroxisome proliferator-activated receptor γ) increases the mRNA expression of GPAT3, which is assocd. with TAG synthesis in adipose tissues. Although GPAT has been considered to be a key enzyme in the prodn. of TAG, unexpected functions have recently been reported, particularly in GPAT2. It is likely that GPAT2 is assocd. with tumorigenesis and normal spermatogenesis. In this review, the physiol. and pathophysiol. roles of the four GPAT isoforms are described, alongside the transcriptional regulation of these enzymes.

    >> More from SciFinder ^®

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXht12gsLnM&md5=9d87984454114060c403f347bee6e782

    
41. 41

    Watanabe, M.; Houten, S. M.; Wang, L.; Moschetta, A.; Mangelsdorf, D. J.; Heyman, R. A.; Moore, D. D.; Auwerx, J. Bile Acids Lower Triglyceride Levels via a Pathway Involving FXR, SHP, and SREBP-1c. J. Clin. Invest. 2004, 113, 1408– 1418,  DOI: 10.1172/JCI21025

    [Crossref], [PubMed], [CAS], Google Scholar

    41

    Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c

    Watanabe, Mitsuhiro; Houten, Sander M.; Wang, Li; Moschetta, Antonio; Mangelsdorf, David J.; Heyman, Richard A.; Moore, David D.; Auwerx, Johan

    Journal of Clinical Investigation (2004), 113 (10), 1408-1418CODEN: JCINAO; ISSN:0021-9738. (American Society for Clinical Investigation)

    The authors explored the effects of bile acids on triglyceride (TG) homeostasis using a combination of mol., cellular, and animal models. Cholic acid (CA) prevents hepatic TG accumulation, VLDL secretion, and elevated serum TG in mouse models of hypertriglyceridemia. At the mol. level, CA decreases hepatic expression of SREBP-1c and its lipogenic target genes. Through the use of mouse mutants for the short heterodimer partner (SHP) and liver X receptor (LXR) α and β, the authors demonstrate the crit. dependence of the redn. of SREBP-1c expression by either natural or synthetic farnesoid X receptor (FXR) agonists on both SHP and LXRα and LXRβ. These results suggest that strategies aimed at increasing FXR activity and the repressive effects of SHP should be explored to correct hypertriglyceridemia.

    >> More from SciFinder ^®

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXktlCltro%253D&md5=c0985e66657b14864821f3ff93e25871

    
42. 42

    Armstrong, L. E.; Guo, G. L. Role of FXR in Liver Inflammation during Nonalcoholic Steatohepatitis. Curr. Pharmacol. Rep. 2017, 3, 92– 100,  DOI: 10.1007/s40495-017-0085-2

    [Crossref], [PubMed], [CAS], Google Scholar

    42

    Role of FXR in Liver Inflammation During Nonalcoholic Steatohepatitis

    Armstrong, Laura E.; Guo, Grace L.

    Current Pharmacology Reports (2017), 3 (2), 92-100CODEN: CPRUG8; ISSN:2198-641X. (Springer International Publishing AG)

    Purpose of Review: About 15-25% of patients with simple steatosis of nonalcoholic fatty liver disease progresses to nonalcoholic steatohepatitis (NASH), and the underlying mechanism for this progression has not been elucidated. NASH ultimately could progress to cirrhosis, an irreversible condition. Recent Findings: Farnesoid X receptor (FXR) has been studied for its role in modulating inflammation, and the expression of FXR is down-regulated during NASH development. FXR deficiency has shown to progress and exacerbate NASH development, and FXR activation has been protective against liver inflammation assocd. with NASH. The expression of factors in both the adaptive and innate immune response in the liver are regulated in a FXR-dependent and -independent manner. Summary: Therefore, understanding key signaling pathways of liver inflammation in NASH is important to det. essential components that predispose, progress, or exacerbate NASH. FXR has been identified as a therapeutic target for NASH to prevent liver inflammation.

    >> More from SciFinder ^®

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXjsFGjtLc%253D&md5=5319ce0ede8357d06f603d3f5f57538d

    
43. 43

    Sinal, C. J.; Tohkin, M.; Miyata, M.; Ward, J. M.; Lambert, G.; Gonzalez, F. J. Targeted Disruption of the Nuclear Receptor FXR/BAR Impairs Bile Acid and Lipid Homeostasis. Cell 2000, 102, 731– 744,  DOI: 10.1016/S0092-8674(00)00062-3

    [Crossref], [PubMed], [CAS], Google Scholar

    43

    Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis

    Sinal, Christopher J.; Tohkin, Masahiro; Miyata, Masaaki; Ward, Jerrold M.; Lambert, Gilles; Gonzalez, Frank J.

    Cell (Cambridge, Massachusetts) (2000), 102 (6), 731-744CODEN: CELLB5; ISSN:0092-8674. (Cell Press)

    Mice lacking the nuclear bile acid receptor FXR/BAR developed normally and were outwardly identical to wild-type littermates. FXR/BAR null mice were distinguished from wild-type mice by elevated serum bile acid, cholesterol, and triglycerides, increased hepatic cholesterol and triglycerides, and a proatherogenic serum lipoprotein profile. FXR/BAR null mice also had reduced bile acid pools and reduced fecal bile acid excretion due to decreased expression of the major hepatic canalicular bile acid transport protein. Bile acid repression and induction of cholesterol 7α-hydroxylase and the ileal bile acid binding protein, resp., did not occur in FXR/BAR null mice, establishing the regulatory role of FXR/BAR for the expression of these genes in vivo. These data demonstrate that FXR/BAR is crit. for bile acid and lipid homeostasis by virtue of its role as an intracellular bile acid sensor.

    >> More from SciFinder ^®

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXmvFShtr8%253D&md5=25400bd9b9ae3957aab04c534007d9c0

    
44. 44

    Jiang, C.; Xie, C.; Li, F.; Zhang, L.; Nichols, R. G.; Krausz, K. W.; Cai, J.; Qi, Y.; Fang, Z. Z.; Takahashi, S.; Tanaka, N.; Desai, D.; Amin, S. G.; Albert, I.; Patterson, A. D.; Gonzalez, F. J. Intestinal Farnesoid X Receptor Signaling Promotes Nonalcoholic Fatty Liver Disease. J. Clin. Invest. 2015, 125, 386– 402,  DOI: 10.1172/JCI76738

    [Crossref], [PubMed], [CAS], Google Scholar

    44

    Intestinal farnesoid X receptor signaling promotes nonalcoholic fatty liver disease

    Jiang Changtao; Xie Cen; Li Fei; Zhang Limin; Nichols Robert G; Krausz Kristopher W; Cai Jingwei; Qi Yunpeng; Fang Zhong-Ze; Takahashi Shogo; Tanaka Naoki; Desai Dhimant; Amin Shantu G; Albert Istvan; Patterson Andrew D; Gonzalez Frank J

    The Journal of clinical investigation (2015), 125 (1), 386-402 ISSN:.

    Nonalcoholic fatty liver disease (NAFLD) is a major worldwide health problem. Recent studies suggest that the gut microbiota influences NAFLD pathogenesis. Here, a murine model of high-fat diet-induced (HFD-induced) NAFLD was used, and the effects of alterations in the gut microbiota on NAFLD were determined. Mice treated with antibiotics or tempol exhibited altered bile acid composition, with a notable increase in conjugated bile acid metabolites that inhibited intestinal farnesoid X receptor (FXR) signaling. Compared with control mice, animals with intestine-specific Fxr disruption had reduced hepatic triglyceride accumulation in response to a HFD. The decrease in hepatic triglyceride accumulation was mainly due to fewer circulating ceramides, which was in part the result of lower expression of ceramide synthesis genes. The reduction of ceramide levels in the ileum and serum in tempol- or antibiotic-treated mice fed a HFD resulted in downregulation of hepatic SREBP1C and decreased de novo lipogenesis. Administration of C16:0 ceramide to antibiotic-treated mice fed a HFD reversed hepatic steatosis. These studies demonstrate that inhibition of an intestinal FXR/ceramide axis mediates gut microbiota-associated NAFLD development, linking the microbiome, nuclear receptor signaling, and NAFLD. This work suggests that inhibition of intestinal FXR is a potential therapeutic target for NAFLD treatment.

    >> More from SciFinder ^®

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2MznsVGnug%253D%253D&md5=4b32e428e075fe94c44576c376431404

    
45. 45

    Xie, C.; Jiang, C.; Shi, J.; Gao, X.; Sun, D.; Sun, L.; Wang, T.; Takahashi, S.; Anitha, M.; Krausz, K. W.; Patterson, A. D.; Gonzalez, F. J. An Intestinal Farnesoid X Receptor-Ceramide Signaling Axis Modulates Hepatic Gluconeogenesis in Mice. Diabetes 2017, 66, 613– 626,  DOI: 10.2337/db16-0663

    [Crossref], [PubMed], [CAS], Google Scholar

    45

    An intestinal farnesoid X receptor-ceramide signaling axis modulates hepatic gluconeogenesis in mice

    Xie, Cen; Jiang, Changtao; Shi, Jingmin; Gao, Xiaoxia; Sun, Dongxue; Sun, Lulu; Wang, Ting; Takahashi, Shogo; Anitha, Mallappa; Krausz, Kristopher W.; Patterson, Andrew D.; Gonzalez, Frank J.

    Diabetes (2017), 66 (3), 613-626CODEN: DIAEAZ; ISSN:0012-1797. (American Diabetes Association, Inc.)

    Increasing evidence supports the view that intestinal farnesoid X receptor (FXR) is involved in glucose tolerance and that FXR signaling can be profoundly impacted by the gut microbiota. Selective manipulation of the gut microbiota-FXR signaling axis was reported to significantly impact glucose intolerance, but the precise mol. mechanism remains largely unknown. Here, caffeic acid phenethyl ester (CAPE), an over-the-counter dietary supplement and an inhibitor of bacterial bile salt hydrolase, increased levels of intestinal tauro-β-muricholic acid, which selectively suppresses intestinal FXR signaling. Intestinal FXR inhibition decreased ceramide levels by suppressing expression of genes involved in ceramide synthesis specifically in the intestinal ileum epithelial cells. The lower serum ceramides mediated decreased hepatic mitochondrial acetyl-CoA levels and pyruvate carboxylase (PC) activities and attenuated hepatic gluconeogenesis, independent of body wt. change and hepatic insulin signaling in vivo; this was reversed by treatment of mice with ceramides or the FXR agonist GW4064. Ceramides substantially attenuated mitochondrial citrate synthase activities primarily through the induction of endoplasmic reticulum stress, which triggers increased hepatic mitochondrial acetyl-CoA levels and PC activities. These results reveal a mechanism by which the dietary supplement CAPE and intestinal FXR regulates hepatic gluconeogenesis and suggest that inhibiting intestinal FXR is a strategy for treating hyperglycemia.

    >> More from SciFinder ^®

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXpvVOiu7s%253D&md5=ebcff94cbd0acdf89715251b79b86206

    
46. 46

    Gonzalez, F. J.; Jiang, C.; Patterson, A. D. An Intestinal Microbiota-Farnesoid X Receptor Axis Modulates Metabolic Disease. Gastroenterology 2016, 151, 845– 859,  DOI: 10.1053/j.gastro.2016.08.057

    [Crossref], [PubMed], [CAS], Google Scholar

    46

    An Intestinal Microbiota-Farnesoid X Receptor Axis Modulates Metabolic Disease

    Gonzalez, Frank J.; Jiang, Changtao; Patterson, Andrew D.

    Gastroenterology (2016), 151 (5), 845-859CODEN: GASTAB; ISSN:0016-5085. (Elsevier)

    The gut microbiota is assocd. with metabolic diseases including obesity, insulin resistance, and nonalcoholic fatty liver disease, as shown by correlative studies and by transplant of microbiota from obese humans and mice into germ-free mice. Modification of the microbiota by treatment of high-fat diet (HFD)-fed mice with tempol or antibiotics resulted in decreased adverse metabolic phenotypes. This was owing to lower levels of the genera Lactobacillus and decreased bile salt hydrolase (BSH) activity. The decreased BSH resulted in increased levels of tauro-β-muricholic acid (MCA), a substrate of BSH and a potent farnesoid X receptor (FXR) antagonist. Mice lacking expression of FXR in the intestine were resistant to HFD-induced obesity, insulin resistance, and nonalcoholic fatty liver disease, thus confirming that intestinal FXR is involved in the potentiation of metabolic disease. A potent intestinal FXR antagonist, glycine-β-MCA (Gly-MCA), which is resistant to BSH, was developed, which, when administered to HFD-treated mice, mimics the effect of the altered microbiota on HFD-induced metabolic disease. Gly-MCA had similar effects on genetically obese leptin-deficient mice. The decrease in adverse metabolic phenotype by tempol, antibiotics, and Gly-MCA was caused by decreased serum ceramides. Mice lacking FXR in the intestine also have lower serum ceramide levels, and are resistant to HFD-induced metabolic disease, and this was reversed by injection of C16:0 ceramide. In mouse ileum, because of the presence of endogenous FXR agonists produced in the liver, FXR target genes involved in ceramide synthesis are activated and when Gly-MCA is administered they are repressed, which likely accounts for the decrease in serum ceramides. These studies show that ceramides produced in the ileum under control of FXR influence metabolic diseases.

    >> More from SciFinder ^®

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhslKnurnI&md5=64a62ca220d79ee06c9bbdd64d0fcf93

    
47. 47

    Jiang, C.; Xie, C.; Lv, Y.; Li, J.; Krausz, K. W.; Shi, J.; Brocker, C. N.; Desai, D.; Amin, S. G.; Bisson, W. H.; Liu, Y.; Gavrilova, O.; Patterson, A. D.; Gonzalez, F. J. Intestine-Selective Farnesoid X Receptor Inhibition Improves Obesity-Related Metabolic Dysfunction. Nat. Commun. 2015, 6, 10166,  DOI: 10.1038/ncomms10166

    [Crossref], [PubMed], [CAS], Google Scholar

    47

    Intestine-selective farnesoid X receptor inhibition improves obesity-related metabolic dysfunction

    Jiang, Changtao; Xie, Cen; Lv, Ying; Li, Jing; Krausz, Kristopher W.; Shi, Jingmin; Brocker, Chad N.; Desai, Dhimant; Amin, Shantu G.; Bisson, William H.; Liu, Yulan; Gavrilova, Oksana; Patterson, Andrew D.; Gonzalez, Frank J.

    Nature Communications (2015), 6 (), 10166CODEN: NCAOBW; ISSN:2041-1723. (Nature Publishing Group)

    The farnesoid X receptor (FXR) regulates bile acid, lipid and glucose metab. Here we show that treatment of mice with glycine-β-muricholic acid (Gly-MCA) inhibits FXR signalling exclusively in intestine, and improves metabolic parameters in mouse models of obesity. Gly-MCA is a selective high-affinity FXR inhibitor that can be administered orally and prevents, or reverses, high-fat diet-induced and genetic obesity, insulin resistance and hepatic steatosis in mice. The high-affinity FXR agonist GW4064 blocks Gly-MCA action in the gut, and intestine-specific Fxr-null mice are unresponsive to the beneficial effects of Gly-MCA. Mechanistically, the metabolic improvements with Gly-MCA depend on reduced biosynthesis of intestinal-derived ceramides, which directly compromise beige fat thermogenic function. Consequently, ceramide treatment reverses the action of Gly-MCA in high-fat diet-induced obese mice. We further show that FXR signalling in ileum biopsies of humans pos. correlates with body mass index. These data suggest that Gly-MCA may be a candidate for the treatment of metabolic disorders.

    >> More from SciFinder ^®

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXitVWqtb3P&md5=f3505f8cf1853ef9bcceafecdc364869

    
48. 48

    Aldini, R.; Roda, A.; Montagnani, M.; Cerre, C.; Pellicciari, R.; Roda, E. Relationship Between Structure and Intestinal Absorption of Bile Acids with a Steroid or Side-Chain Modification. Steroids 1996, 61, 590– 597,  DOI: 10.1016/S0039-128X(96)00119-5

    [Crossref], [PubMed], [CAS], Google Scholar

    48

    Relationship between structure and intestinal absorption of bile acids with a steroid or side-chain modification

    Aldini, Rita; Roda, Aldo; Montagnani, Marco; Cerre, Carolina; Pellicciari, Roberto; Roda, Enrico

    Steroids (1996), 61 (10), 590-597CODEN: STEDAM; ISSN:0039-128X. (Elsevier)

    A structure-activity relation for bile acid (BA) intestinal absorption is known to exist. To better understand the BA structural requirements for optimal BA intestinal absorption, rabbit ileal perfusion studies were performed. Unconjugated BA: Ursodeoxycholic (UDCA) and ursocholic acid (UCA) with Me (6MUDCA and 6MUCA) or fluoro group (6FUDCA and 6FUCA) in the 6 position and UCA with a Me group in 23 position (23MUCA) were compared with unconjugated UDCA, UCA, deoxycholic (DCA), chenodeoxycholic (CDCA), hyocholic (HCA), and hyodeoxycholic (HDCA) acid. BA lipophilicity was evaluated by their octanol water partition coeff. Taurine-conjugated UDCA and UCA with a Me group in the 23 position (T23MUDCA and T23MUCA) were compared with the corresponding taurine-conjugated natural analogs. An analog of glycine-conjugated UDCA with the C24 amide bond replaced by a -CO-CH2- in the 24 position (24PUDCA) was studied and results were compared with the natural form (GUDCA). Unconjugated BA absorption was dose dependent (i.e., passive) and followed their lipophilicity: DCA > 6MUDCA > CDCA > HDCA > UDCA > HCA > 6FUDCA > 6MUCA > 6FUCA > UCA. Conjugated BA absorption was active, and Vmax was in the following order: TCA > TUDCA > TUCA > T23MUCA > T23MUDCA > 24PUDCA > GUDCA. 24PUDCA transport was also active and higher than GUDCA. Passive transport is dependent on BA lipophilicity. Conjugated BAs are actively transported, and the presence of a 23-C Me group does not improve transport when compared with the natural analogs. The substitution of the C24 amide bond with a -CO-CH2-still affords interaction of the BA with the intestinal transport carrier.

    >> More from SciFinder ^®

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XmsFShurs%253D&md5=d4ea55a2a50ca6da64ff04b674612ab0

    
49. 49

    Roda, A.; Pellicciari, R.; Cerre, C.; Polimeni, C.; Sadeghpour, B.; Marinozzi, M.; Forti, G. C.; Sapigni, E. New 6-Substituted Bile Acids: Physico-Chemical and Biological Properties of 6α-Methyl Ursodeoxycholic Acid and 6α-Methyl-7-Epicholic Acid. J. Lipid Res. 1994, 35, 2268– 2279

    [PubMed], [CAS], Google Scholar

    49

    New 6-substituted bile acids: physico-chemical and biological properties of 6α-methyl ursodeoxycholic acid and 6α-methyl-7-epicholic acid

    Roda, Aldo; Pellicciari, Roberto; Cerre, Carolina; Polimeni, Carla; Sadeghpour, Bahman; Marinozzi, Maura; Forti, Giorgio Cantelli; Sapigni, Ester

    Journal of Lipid Research (1994), 35 (12), 2268-79CODEN: JLPRAW; ISSN:0022-2275. (Lipid Research, Inc.)

    New analogs of ursodeoxycholic acid and 7-epicholic acid contg. a 6α-Me group were synthesized, and their physico-chem. properties were studied and compared with those of their natural analogs. The 6α-Me group slightly increases the lipophilicity and slightly lowers the crit. micellar concn. with respect to the corresponding natural analogs. Simulated bile 50% enriched with 6α-Me ursodeoxycholic acid, with a total bile acid/phospholipid ratio of 10/1, demonstrated a higher cholesterol-holding capacity and a faster cholesterol gallstone dissoln. rate with respect to ursodeoxycholic acid, while 6α-methyl-7-epicholic acid and 7-epicholic acid were much less efficient in these processes. The 6α-Me analogs were highly stable toward 7-dehydroxylation when incubated with human stool in anaerobic conditions. Their transport, metab., and effect on biliary lipid secretion were evaluated both in rats and hamsters after acute i.v. and intraduodenal infusion at a dose of 10 μmol/min per kg. In both species, 6α-Me ursodeoxycholic acid is efficiently secreted in bile, with a cumulative recovery similar to that of ursodeoxycholic acid. The only metabolites of 6α-Me ursodeoxycholic acid identified were its glycine and taurine amidated forms. 6α-Methyl-7-epicholic acid was efficiently secreted into bile when infused i.v., and to a lesser extent when infused intraduodenally, in both rats and hamsters; it was secreted in bile as amidate and also as free acid. When 6α-Me ursodeoxycholic acid, 6α-methyl-7-epicholic acid, ursodeoxycholic acid, and 7-epicholic acid were chronically administered to hamsters (for 3 wk, at a dose of 50 mg/kg per day) their accumulation in gallbladder bile was, resp., 25.1%, 4.0%, 15.2%, and 3.4% of the total bile acids. In conclusion, of the two analogs, only 6α-Me ursodeoxycholic acid shows potential as a cholesterol gallstone-dissolving agent. In this regard, its most important properties are moderate lipophilicity, good metabolic stability, and better conservation in the enterohepatic circulation, with respect to ursodeoxycholic acid.

    >> More from SciFinder ^®

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXivFemsLo%253D&md5=32ef0ffaba76f22696a09d054afa8bb1

    
50. 50

    Pellicciari, R.; Fiorucci, S.; Camaioni, E.; Clerici, C.; Costantino, G.; Maloney, P. R.; Morelli, A.; Parks, D. J.; Willson, T. M. 6α-ethyl-chenodeoxycholic Acid (6-ECDCA), a Potent and Selective FXR Agonist Endowed with Anticholestatic Activity. J. Med. Chem. 2002, 45, 3569– 3572,  DOI: 10.1021/jm025529g

    [ACS Full Text ], [CAS], Google Scholar

    50

    6α-Ethyl-Chenodeoxycholic Acid (6-ECDCA), a Potent and Selective FXR Agonist Endowed with Anticholestatic Activity

    Pellicciari, Roberto; Fiorucci, Stefano; Camaioni, Emidio; Clerici, Carlo; Costantino, Gabriele; Maloney, Patrick R.; Morelli, Antonio; Parks, Derek J.; Willson, Timothy M.

    Journal of Medicinal Chemistry (2002), 45 (17), 3569-3572CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

    A series of 6α-alkyl-substituted analogs I (R = Me, Et, Pr, Bn) of chenodeoxycholic acid (CDCA) were synthesized and evaluated as potential farnesoid X receptor (FXR) ligands. Among them, 6α-ethyl-chenodeoxycholic acid (6-ECDCA) I (R = Et) was shown to be a very potent and selective FXR agonist (EC50 = 99 nM) and to be endowed with anticholeretic activity in an in vivo rat model of cholestasis.

    >> More from SciFinder ^®

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XlsVSgs7s%253D&md5=0b6652c1ad92eb681bf96a7df7b2d367

    
51. 51

    Intercept http://ir.interceptpharma.com/news-releases/news-release-details/intercept-announces-positive-topline-results-pivotal-phase-3 (accessed Nov 26, 2019).

    Google Scholar

    There is no corresponding record for this reference.

    
52. 52

    Ratziu, V.; Sanyal, A. J.; Loomba, R.; Rinella, M.; Harrison, S.; Anstee, Q. M.; Goodman, Z.; Bedossa, P.; MacConell, L.; Shringarpure, R.; Shah, A.; Younossi, Z. REGENERATE: Design of a Pivotal, Randomised, Phase 3 Study Evaluating the Safety and Efficacy of Obeticholic Acid in Patients with Fibrosis due to Nonalcoholic Steatohepatitis. Contemp. Clin. Trials 2019, 84, 105803,  DOI: 10.1016/j.cct.2019.06.017

    [Crossref], [PubMed], [CAS], Google Scholar

    52

    REGENERATE: Design of a pivotal, randomised, phase 3 study evaluating the safety and efficacy of obeticholic acid in patients with fibrosis due to nonalcoholic steatohepatitis

    Ratziu Vlad; Sanyal Arun J; Loomba Rohit; Rinella Mary; Harrison Stephen; Anstee Quentin M; Goodman Zachary; Younossi Zobair; Bedossa Pierre; MacConell Leigh; Shringarpure Reshma; Shah Amrik

    Contemporary clinical trials (2019), 84 (), 105803 ISSN:.

    BACKGROUND: Nonalcoholic steatohepatitis (NASH) is a chronic, progressive, and severe form of nonalcoholic fatty liver disease. In FLINT, obeticholic acid (OCA) treatment improved multiple histological NASH features. The design and endpoints of REGENERATE, an ongoing phase 3 study, further evaluate OCA treatment in patients with fibrosis due to NASH. AIMS: The Month 18 interim analysis assesses the effect of OCA on liver histology, defined as improvement of fibrosis by ≥1 stage with no worsening of NASH or resolution of NASH with no worsening of fibrosis. The end-of-study analyses evaluate the effect of OCA on mortality, liver-related clinical outcomes, and long-term safety. METHODS: REGENERATE is a pivotal, long-term study of ~2400 patients with NASH, including ~2100 patients with stage 2 or 3 liver fibrosis. Additionally, ~300 patients with stage 1 fibrosis and ≥1 accompanying comorbidity are included to gather information on the safety of OCA and liver disease progression. Patients are randomised 1:1:1 to receive placebo or OCA (10 or 25 mg). A liver biopsy evaluation occurs at screening, Months 18 and 48, and end of study. The duration of the study is dependent upon accrual of a predetermined number of clinical outcome events. CONCLUSIONS: REGENERATE is designed in conjunction with regulatory authorities to support regulatory approvals in NASH. This robust phase 3 study assesses the effect of OCA on liver histology as a surrogate for transplant-free survival and liver-related outcomes, including progression to cirrhosis and mortality, and will ultimately assess clinical benefit through specific evaluation of these outcomes. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov with the identifier NCT02548351.

    >> More from SciFinder ^®

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3MzivV2isA%253D%253D&md5=e269c8a97a49c0880998f9b9cde438b1

    
53. 53

    Alemi, F.; Kwon, E.; Poole, D. P.; Lieu, T.; Lyo, V.; Cattaruzza, F.; Cevikbas, F.; Steinhoff, M.; Nassini, R.; Materazzi, S.; Guerrero-Alba, R.; Valdez-Morales, E.; Cottrell, G. S.; Schoonjans, K.; Geppetti, P.; Vanner, S. J.; Bunnett, N. W.; Corvera, C. U. The TGR5 Receptor Mediates Bile Acid-Induced Itch and Analgesia. J. Clin. Invest. 2013, 123, 1513– 1530,  DOI: 10.1172/JCI64551

    [Crossref], [PubMed], [CAS], Google Scholar

    53

    The TGR5 receptor mediates bile acid-induced itch and analgesia

    Alemi, Farzad; Kwon, Edwin; Poole, Daniel P.; Lieu, TinaMarie; Lyo, Victoria; Cattaruzza, Fiore; Cevikbas, Ferda; Steinhoff, Martin; Nassini, Romina; Materazzi, Serena; Guerrero-Alba, Raquel; Valdez-Morales, Eduardo; Cottrell, Graeme S.; Schoonjans, Kristina; Geppetti, Pierangelo; Vanner, Stephen J.; Bunnett, Nigel W.; Corvera, Carlos U.

    Journal of Clinical Investigation (2013), 123 (4), 1513-1530CODEN: JCINAO; ISSN:0021-9738. (American Society for Clinical Investigation)

    Patients with cholestatic disease exhibit pruritus and analgesia, but the mechanisms underlying these symptoms are unknown. We report that bile acids, which are elevated in the circulation and tissues during cholestasis, cause itch and analgesia by activating the GPCR TGR5. TGR5 was detected in peptidergic neurons of mouse dorsal root ganglia and spinal cord that transmit itch and pain, and in dermal macrophages that contain opioids. Bile acids and a TGR5-selective agonist induced hyperexcitability of dorsal root ganglia neurons and stimulated the release of the itch and analgesia transmitters gastrin-releasing peptide and leucine-enkephalin. Intradermal injection of bile acids and a TGR5-selective agonist stimulated scratching behavior by gastrin-releasing peptide- and opioid-dependent mechanisms in mice. Scratching was attenuated in Tgr5-KO mice but exacerbated in Tgr5-Tg mice (overexpressing mouse TGR5), which exhibited spontaneous pruritus. Intraplantar and intrathecal injection of bile acids caused analgesia to mech. stimulation of the paw by an opioid-dependent mechanism. Both peripheral and central mechanisms of analgesia were absent from Tgr5-KO mice. Thus, bile acids activate TGR5 on sensory nerves, stimulating the release of neuropeptides in the spinal cord that transmit itch and analgesia. These mechanisms could contribute to pruritus and painless jaundice that occur during cholestatic liver diseases.

    >> More from SciFinder ^®

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXlvVKhsL8%253D&md5=cd059ff96952743f065d002d7eb2d1cd

    
54. 54

    Guo, C.; Chen, W. D.; Wang, Y. D. TGR5, Not Only a Metabolic Regulator. Front. Physiol. 2016, 7, 646,  DOI: 10.3389/fphys.2016.00646

    [Crossref], [PubMed], [CAS], Google Scholar

    54

    TGR5, Not Only a Metabolic Regulator

    Guo Cong; Wang Yan-Dong; Chen Wei-Dong

    Frontiers in physiology (2016), 7 (), 646 ISSN:1664-042X.

    G-protein-coupled bile acid receptor, Gpbar1 (TGR5), is a member of G-protein-coupled receptor (GPCR) superfamily. High levels of TGR5 mRNA were detected in several tissues such as small intestine, stomach, liver, lung, especially in placenta and spleen. TGR5 is not only the receptor for bile acids, but also the receptor for multiple selective synthetic agonists such as 6α-ethyl-23(S)-methyl-cholic acid (6-EMCA, INT-777) and a series of 4-benzofuranyloxynicotinamde derivatives to regulate different signaling pathways such as nuclear factor κB (NF-κB), AKT, and extracellular signal-regulated kinases (ERK). TGR5, as a metabolic regulator, is involved in energy homeostasis, bile acid homeostasis, as well as glucose metabolism. More recently, our group and others have extended the functions of TGR5 to more than metabolic regulation, which include inflammatory response, cancer and liver regeneration. These findings highlight TGR5 as a potential drug target for different diseases. This review summarizes the basic information of TGR5 and its new functions.

    >> More from SciFinder ^®

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1c7lt12jsA%253D%253D&md5=2a2d5f79bf1c7d0f851b0874c76232cc

    
55. 55

    Wang, G.; Or, Y. S.; Shen, R.; Long, J.; Dai, P.; Xing, X.; He, J. Bile Acid Derivatives as PXR/TGR5 Agonists and Methods of Use Thereof. International Patent WO2016086218, 2016.

    Google Scholar

    There is no corresponding record for this reference.

    
56. 56

    Chau, M.; Li, Y.; Roqueta-Rivera, M.; Garlick, E.; Shen, R. Characterization of EDP-305, a Highly Potent and Selective Farnesoid X Receptor Agonist, for the Treatment of Non-Alcoholic Steatohepatitis. International Journal of Gastroenterology 2019, 3, 4– 16,  DOI: 10.11648/j.ijg.20190301.12

    [Crossref], Google Scholar

    There is no corresponding record for this reference.

    
57. 57

    Ahmad, A.; Sanderson, K.; Dickerson, D.; Adda, N. Pharmacokinetics, Pharmacodynamics, and Safety of EDP-305 in Healthy and Presumptive NAFLD Subjects. Presented at the European Associate for the Study of the Liver International Liver Conference, Paris, France, April 11–15, 2018; FRI-489.

    Google Scholar

    There is no corresponding record for this reference.

    
58. 58

    Enanta https://www.enanta.com/investors/news-releases/press-release/2019/Enanta-Announces-Positive-Results-of-ARGON-1-Study-of-its-lead-FXR-Agonist-EDP-305-for-the-Treatment-of-NASH/default.aspx (accessed Sept 25, 2019).

    Google Scholar

    There is no corresponding record for this reference.

    
59. 59

    Gege, C.; Hambruch, E.; Hambruch, N.; Kinzel, O.; Kremoser, C. Nonsteroidal FXR Ligands: Current Status and Clinical Applications. In Bile Acids And Their Receptors, Fiorucci, S., Distrutti, E., Eds.; Springer: Switzerland, 2019; pp 167– 205.

    [Crossref], Google Scholar

    There is no corresponding record for this reference.

    
60. 60

    Maloney, P. R.; Parks, D. J.; Haffner, C. D.; Fivush, A. M.; Chandra, G.; Plunket, K. D.; Creech, K. L.; Moore, L. B.; Wilson, J. G.; Lewis, M. C.; Jones, S. A.; Willson, T. M. Identification of a Chemical Tool for the Orphan Nuclear Receptor FXR. J. Med. Chem. 2000, 43, 2971– 2974,  DOI: 10.1021/jm0002127

    [ACS Full Text ], [CAS], Google Scholar

    60

    Identification of a Chemical Tool for the Orphan Nuclear Receptor FXR

    Maloney, Patrick R.; Parks, Derek J.; Haffner, Curt D.; Fivush, Adam M.; Chandra, Gyan; Plunket, Kelli D.; Creech, Katrina L.; Moore, Linda B.; Wilson, Joan G.; Lewis, Michael C.; Jones, Stacey A.; Willson, Timothy M.

    Journal of Medicinal Chemistry (2000), 43 (16), 2971-2974CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

    The authors have identified the first high-affinity nonsteroidal FXR nuclear receptor agonist through use of high-throughput screening and combinatorial chem. This agonist, GW4064, will be a valuable chem. tool for studying the role of FXR in mammalian physiol. and disease. The data also establishes triglyceride lowering as a surrogate pharmacol. response to the activation of FXR receptor.

    >> More from SciFinder ^®

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXltVSiur0%253D&md5=111bd63144e2af62eee81b4d706a2672

    
61. 61

    Genin, M. J.; Bueno, A. B.; Agejas Francisco, J.; Manninen, P. R.; Bocchinfuso, W. P.; Montrose-Rafizadeh, C.; Cannady, E. A.; Jones, T. M.; Stille, J. R.; Raddad, E.; Reidy, C.; Cox, A.; Michael, M. D.; Michael, L. F. Discovery of 6-(4-{[5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl]methoxy}piperidin-1-yl)- 1-methyl-1H-indole-3-carboxylic Acid: A Novel FXR Agonist for the Treatment of Dyslipidemia. J. Med. Chem. 2015, 58, 9768– 9772,  DOI: 10.1021/acs.jmedchem.5b01161

    [ACS Full Text ], [CAS], Google Scholar

    61

    Discovery of 6-(4-{[5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl]methoxy}piperidin-1-yl)-1-methyl-1H-indole-3-carboxylic Acid: A Novel FXR Agonist for the Treatment of Dyslipidemia

    Genin, Michael J.; Bueno, Ana B.; Agejas Francisco, Javier; Manninen, Peter R.; Bocchinfuso, Wayne P.; Montrose-Rafizadeh, Chahrzad; Cannady, Ellen A.; Jones, Timothy M.; Stille, John R.; Raddad, Eyas; Reidy, Charles; Cox, Amy; Michael, M. Dodson; Michael, Laura F.

    Journal of Medicinal Chemistry (2015), 58 (24), 9768-9772CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

    The farnesoid X receptor (FXR) is a member of the "metabolic" subfamily of nuclear receptors. Several FXR agonists have been reported in the literature to have profound effects on plasma lipids in animal models. To discover novel and effective therapies for dyslipidemia and atherosclerosis, the authors have developed a series of potent FXR agonists that robustly lower plasma LDL and vLDL in LDLr-/- mice. To this end the novel piperidinylisoxazole system LY2562175 was discovered. This mol. is a potent and selective FXR agonist in vitro and has robust lipid modulating properties, lowering LDL and triglycerides while raising HDL in preclin. species. The preclin. ADME properties of LY2562175 were consistent with enabling once daily dosing in humans, and it was ultimately advanced to the clinic for evaluation in humans. The synthesis and biol. profile of this mol. is discussed.

    >> More from SciFinder ^®

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhvVehsrbF&md5=cd5b476973a98c33da5a6c25faca2fdf

    
62. 62

    Klucher, K.; Wang, Y.; Halcomb, R.; Fenaux, M. A Novel Farnesoid X Receptor Agonist, TERN-101, Reduces Liver Steatosis, Inflammation, Ballooning and Fibrosis in a Murine Model of Non-Alcoholic Steatohepatitis. Presented at the European Associate for the Study of the Liver International Liver Conference, Vienna, Austria, April 10–14, 2019; FRI-313.

    Google Scholar

    There is no corresponding record for this reference.

    
63. 63

    TERN-101 Licensing. https://www.businesswire.com/news/home/20180404005033/en/Terns-Pharmaceuticals-Acquires-Global-Exclusive-Rights-Develop (accessed Sept 25, 2019).

    Google Scholar

    There is no corresponding record for this reference.

    
64. 64

    Terns Pharmaceuticals: TERN-101. https://www.ternspharma.com/6-13-19-terns-pharmaceuticals-initiates-a-phase-1-clinical-trial-of-tern-101 (accessed Sept 25, 2019).

    Google Scholar

    There is no corresponding record for this reference.

    
65. 65

    Kinzel, O.; Steeneck, C.; Kremoser, C. Novel FXR (NR1H4) Binding and Activity Modulating Compounds. International Patent WO2013007387, 2013.

    Google Scholar

    There is no corresponding record for this reference.

    
66. 66

    Hambruch, E.; Liles, J.; Kinzel, O.; Birkel, M.; French, D.; Hollenback, D.; Djedjos, S.; Kirby, B.; Hornherger, M.; Walkins, W.; Kremoser, C. How to Develop a Differentiated FXR Agonist: GS-9674 Shows a Reduced Side Effect Profile in Mice, Monkeys and Human Phase 1 Studies Compared to Its Predecessor Px-102. Presented at the European Associate for the Study of the Liver International Liver Conference, Vienna, Austria, April 10–14, 2019; FRI-303.

    Google Scholar

    There is no corresponding record for this reference.

    
67. 67

    Patel, K.; Harrison, S. A.; Trotter, J. F.; Herring, R.; Rojter, S. E.; Kayali, Z.; Shiffman, M. L.; Freilich, B. L.; Lawitz, E. J.; Harting, E.; Nguyen, T.; Chung, C.; Subramanian, M.; Myers, R. P.; Middleton, M. S.; Rinella, M. E. M.; Noureddin, M. The Non-Steroidal FXR Agonist GS-9674 Leads to Significant Reductions in Hepatic Steatosis, Serum Bile Acids, and Liver Biochemistry in a Phase 2, Randomized, Placebo-Controlled Trial of Patients with NASH. Presented at the American Association for the Study of Liver Diseases, San Francisco, USA, November 9–13, 2018; 736.

    Google Scholar

    There is no corresponding record for this reference.

    
68. 68

    Tully, D. C.; Rucker, P. V.; Chianelli, D.; Williams, J.; Vidal, A.; Alper, P. B.; Mutnick, D.; Bursulaya, B.; Schmeits, J.; Wu, X.; Bao, D.; Zoll, J.; Kim, Y.; Groessl, T.; McNamara, P.; Seidel, H. M.; Molteni, V.; Liu, B.; Phimister, A.; Joseph, S. B.; Laffitte, B. Discovery of Tropifexor (LJN452), a Highly Potent Non-Bile Acid FXR Agonist for the Treatment of Cholestatic Liver Diseases and Nonalcoholic Steatohepatitis (NASH). J. Med. Chem. 2017, 60, 9960– 9973,  DOI: 10.1021/acs.jmedchem.7b00907

    [ACS Full Text ], [CAS], Google Scholar

    68

    Discovery of Tropifexor (LJN452), a Highly Potent Non-bile Acid FXR Agonist for the Treatment of Cholestatic Liver Diseases and Nonalcoholic Steatohepatitis (NASH)

    Tully, David C.; Rucker, Paul V.; Chianelli, Donatella; Williams, Jennifer; Vidal, Agnes; Alper, Phil B.; Mutnick, Daniel; Bursulaya, Badry; Schmeits, James; Wu, Xiangdong; Bao, Dingjiu; Zoll, Jocelyn; Kim, Young; Groessl, Todd; McNamara, Peter; Seidel, H. Martin; Molteni, Valentina; Liu, Bo; Phimister, Andrew; Joseph, Sean B.; Laffitte, Bryan

    Journal of Medicinal Chemistry (2017), 60 (24), 9960-9973CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

    The farnesoid X receptor (FXR) is a nuclear receptor that acts as a master regulator of bile acid metab. and signaling. Activation of FXR inhibits bile acid synthesis and increases bile acid conjugation, transport, and excretion, thereby protecting the liver from the harmful effects of bile accumulation, leading to considerable interest in FXR as a therapeutic target for the treatment of cholestasis and nonalcoholic steatohepatitis. We identified a novel series of highly potent non-bile acid FXR agonists that introduce a bicyclic nortropine-substituted benzothiazole carboxylic acid moiety onto a trisubstituted isoxazole scaffold. Herein, we report the discovery of 1 (tropifexor, LJN452), a novel and highly potent agonist of FXR. Potent in vivo activity was demonstrated in rodent PD models by measuring the induction of FXR target genes in various tissues. Tropifexor has advanced into phase 2 human clin. trials in patients with NASH and PBC.

    >> More from SciFinder ^®

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvVWqur7P&md5=4b7a31f2e17645f3831c4dcbf34dd46c

    
69. 69

    Lucas, K. J.; Lopez, P.; Lawitz, E. J.; Sheikh, A.; Aizenberg, D.; Hsia, S.; Goh, G. B. B.; Vierling, J. M.; Frias, J. P.; White, J.; Eguchi, Y.; Lazas, D.; Neff, G.; Yoneda, M.; Augustin, S.; Kim, W.; Loeffler, J.; Schaefer, F. A.; Lamle, S.; Martic, M.; Brass, C.; Sanyal, A. Tropifexor, a Highly Potent FXR Agonist, Produces Robust and Dose-Dependent Reductions in Hepatic Fat and Serum Alanine Aminotransferase in Patients with Fibrotic NASH after 12 Weeks of Therapy: FLIGHT-FXR Part C Interim Results. Presented at the American Association for the Study of Liver Diseases, Boston, USA, November 13–17, 2019, LO4.

    Google Scholar

    There is no corresponding record for this reference.

    
70. 70

    Chianelli, D.; Liu, X.; Molteni, V.; Nelson, J.; Roland, J. Compositions and Methods for Modulating Farnesoid X Receptors. International Patent WO2015069666, 2015.

    Google Scholar

    There is no corresponding record for this reference.

    
71. 71

    Laffitte, B.; Liu, B.; Kim, Y.; Bao, D.; Zoll, J.; Wu, X.; Badman, M.; Nelson, J.; Rucker, P.; Liu, X.; Chianelli, D.; Tully, D.; Roland, J.; Molteni, V. Development of LMB763, a Novel, Orally Bioavailable, Clinical Farnesoid X Receptor Agonist for the Treatment of Non-Alcoholic Steatohepatitis and Hepatobiliary Disorders. Presented at the European Associate for the Study of the Liver International Liver Conference, Amsterdam, The Netherlands, April 19–23, 2017; THU-378.

    Google Scholar

    There is no corresponding record for this reference.

    
72. 72

    Roche, D.; Kober, G. M.; Contard, F.; Christmann-Franck, S. Benzofurane, Benzothiophene, Benzothiazol Derivatives as FXR Modulators. International Patent WO2009127321, 2009.

    Google Scholar

    There is no corresponding record for this reference.

    
73. 73

    Metacrine https://www.globenewswire.com/news-release/2019/05/29/1856242/0/en/Metacrine-Reports-Positive-Interim-Results-with-Sustained-FXR-Agonist-in-NASH-Patients.html (accessed Sept 25, 2019).

    Google Scholar

    There is no corresponding record for this reference.

    
74. 74

    Mondal, S.; Mugesh, G. Novel Thyroid Hormone Analogues, Enzyme Inhibitors and Mimetics, and their Action. Mol. Cell. Endocrinol. 2017, 458, 91– 104,  DOI: 10.1016/j.mce.2017.04.006

    [Crossref], [PubMed], [CAS], Google Scholar

    74

    Novel thyroid hormone analogues, enzyme inhibitors and mimetics, and their action

    Mondal, Santanu; Mugesh, Govindasamy

    Molecular and Cellular Endocrinology (2017), 458 (), 91-104CODEN: MCEND6; ISSN:0303-7207. (Elsevier Ireland Ltd.)

    A review. Thyroid hormones (THs) play key roles in modulating the overall metab. of the body, protein synthesis, fat metab., neuronal and bone growth, and cardiovascular as well as renal functions. In this review, we discuss on the thyroid hormone synthesis and activation, thyroid hormone receptors (TRs) and mechanism of action, applications of thyroid hormone analogs, particularly the compds. that are selective ligands for TRβ receptors, or enzyme inhibitors for the treatment of thyroidal disorders with a specific focus on thyroid peroxidase and iodothyronine deiodinases. We also discuss on the development of small-mol. deiodinase mimetics and their mechanism of deiodination, as these compds. have the potential to regulate the thyroid hormone levels.

    >> More from SciFinder ^®

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXmsFGlt70%253D&md5=4e4a4fbcf89925c20dec09aa23a7b659

    
75. 75

    Chiamolera, M. I.; Wondisford, F. E. Minireview: Thyrotropin-Releasing Hormone and the Thyroid Hormone Feedback Mechanism. Endocrinology 2009, 150, 1091– 1096,  DOI: 10.1210/en.2008-1795

    [Crossref], [PubMed], [CAS], Google Scholar

    75

    Minireview: thyrotropin-releasing hormone and the thyroid hormone feedback mechanism

    Chiamolera, Maria Izabel; Wondisford, Fredric E.

    Endocrinology (2009), 150 (3), 1091-1096CODEN: ENDOAO; ISSN:0013-7227. (Endocrine Society)

    A review. Thyroid hormone (TH) plays a crit. role in development, growth, and cellular metab. TH prodn. is controlled by a complex mechanism of pos. and neg. regulation. Hypothalamic TSH-releasing hormone (TRH) stimulates TSH secretion from the anterior pituitary. TSH then initiates TH synthesis and release from the thyroid gland. The synthesis of TRH and TSH subunit genes is inhibited at the transcriptional level by TH, which also inhibits posttranslational modification and release of TSH. Although opposing TRH and TH inputs regulate the hypothalamic-pituitary-thyroid axis, TH neg. feedback at the pituitary was thought to be the primary regulator of serum TSH levels. However, study of transgenic animals showed an unexpected, dominant role for TRH in regulating the hypothalamic-pituitary-thyroid axis and an unanticipated involvement of the thyroid hormone receptor ligand-dependent activation function (AF-2) domain in TH neg. regulation. These results are summarized in the review.

    >> More from SciFinder ^®

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXisV2gsbc%253D&md5=47d1df937228bfbbea70276ef120490a

    
76. 76

    Brent, G. A. Mechanisms of Thyroid Hormone Action. J. Clin. Invest. 2012, 122, 3035– 3043,  DOI: 10.1172/JCI60047

    [Crossref], [PubMed], [CAS], Google Scholar

    76

    Mechanisms of thyroid hormone action

    Brent, Gregory A.

    Journal of Clinical Investigation (2012), 122 (9), 3035-3043CODEN: JCINAO; ISSN:0021-9738. (American Society for Clinical Investigation)

    A review. Our understanding of thyroid hormone action has been substantially altered by recent clin. observations of thyroid signaling defects in syndromes of hormone resistance and in a broad range of conditions, including profound mental retardation, obesity, metabolic disorders, and a no. of cancers. The mechanism of thyroid hormone action has been informed by these clin. observations as well as by animal models and has influenced the way we view the role of local ligand availability; tissue and cell-specific thyroid hormone transporters, corepressors, and coactivators; thyroid hormone receptor (TR) isoform-specific action; and cross-talk in metabolic regulation and neural development. In some cases, our new understanding has already been translated into therapeutic strategies, esp. for treating hyperlipidemia and obesity, and other drugs are in development to treat cardiac disease and cancer and to improve cognitive function.

    >> More from SciFinder ^®

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtlChsb3F&md5=93e30b596f1989d574add68b9ab0249a

    
77. 77

    Gereben, B.; Zavacki, A. M.; Ribich, S.; Kim, B. W.; Huang, S. A.; Simonides, W. S.; Zeold, A.; Bianco, A. C. Cellular and Molecular Basis of Deiodinase-Regulated Thyroid Hormone Signaling. Endocr. Rev. 2008, 29, 898– 938,  DOI: 10.1210/er.2008-0019

    [Crossref], [PubMed], [CAS], Google Scholar

    77

    Cellular and molecular basis of deiodinase-regulated thyroid hormone signaling

    Gereben, Balazs; Zavacki, Ann Marie; Ribich, Scott; Kim, Brian W.; Huang, Stephen A.; Simonides, Warner S.; Zeold, Aniko; Bianco, Antonio C.

    Endocrine Reviews (2008), 29 (7), 898-938CODEN: ERVIDP; ISSN:0163-769X. (Endocrine Society)

    A review. The iodothyronine deiodinases initiate or terminate thyroid hormone action and therefore are crit. for the biol. effects mediated by thyroid hormone. Over the years, research has focused on their role in preserving serum levels of the biol. active mol. T3 during iodine deficiency. More recently, a fascinating new role of these enzymes has been unveiled. The activating deiodinase (D2) and the inactivating deiodinase (D3) can locally increase or decrease thyroid hormone signaling in a tissue- and temporal-specific fashion, independent of changes in thyroid hormone serum concns. This mechanism is particularly relevant because deiodinase expression can be modulated by a wide variety of endogenous signaling mols. such as sonic hedgehog, nuclear factor-κB, growth factors, bile acids, hypoxia-inducible factor-1α, as well as a growing no. of xenobiotic substances. In light of these findings, it seems clear that deiodinases play a much broader role than once thought, with great ramifications for the control of thyroid hormone signaling during vertebrate development and metamorphosis, as well as injury response, tissue repair, hypothalamic function, and energy homeostasis in adults.

    >> More from SciFinder ^®

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXmt1yjtQ%253D%253D&md5=042dac3b9953deacc412dceceb673fb7

    
78. 78

    Yen, P. M. Physiological and Molecular Basis of Thyroid Hormone Action. Physiol. Rev. 2001, 81, 1097– 1142,  DOI: 10.1152/physrev.2001.81.3.1097

    [Crossref], [PubMed], [CAS], Google Scholar

    78

    Physiological and molecular basis of thyroid hormone action

    Yen, Paul M.

    Physiological Reviews (2001), 81 (3), 1097-1142CODEN: PHREA7; ISSN:0031-9333. (American Physiological Society)

    A review, with 610 refs. Thyroid hormones (THs) play crit. roles in the differentiation, growth, metab., and physiol. function of virtually all tissues. TH binds to receptors that are ligand-regulatable transcription factors belonging to the nuclear hormone receptor superfamily. Tremendous progress has been made recently in our understanding of the mol. mechanisms that underlie TH action. In this review, we present the major advances in our knowledge of the mol. mechanisms of TH action and their implications for TH action in specific tissues, resistance to thyroid hormone syndrome, and genetically engineered mouse models.

    >> More from SciFinder ^®

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXlt1Ohsrw%253D&md5=7a2a77c42b8df68921fcefb3ab8f77c6

    
79. 79

    Nascimento, A. S.; Dias, S. M.; Nunes, F. M.; Aparicio, R.; Ambrosio, A. L.; Bleicher, L.; Figueira, A. C.; Santos, M. A.; de Oliveira Neto, M.; Fischer, H.; Togashi, M.; Craievich, A. F.; Garratt, R. C.; Baxter, J. D.; Webb, P.; Polikarpov, I. Structural Rearrangements in the Thyroid Hormone Receptor Hinge Domain and their Putative Role in the Receptor Function. J. Mol. Biol. 2006, 360, 586– 598,  DOI: 10.1016/j.jmb.2006.05.008

    [Crossref], [PubMed], [CAS], Google Scholar

    79

    Structural Rearrangements in the Thyroid Hormone Receptor Hinge Domain and Their Putative Role in the Receptor Function

    Nascimento, Alessandro S.; Dias, Sandra Martha Gomes; Nunes, Fabio M.; Aparicio, Ricardo; Ambrosio, Andre L. B.; Bleicher, Lucas; Figueira, Ana Carolina M.; Santos, Maria Auxiliadora M.; de Oliveira Neto, Mario; Fischer, Hannes; Togashi, Marie; Craievich, Aldo F.; Garratt, Richard C.; Baxter, John D.; Webb, Paul; Polikarpov, Igor

    Journal of Molecular Biology (2006), 360 (3), 586-598CODEN: JMOBAK; ISSN:0022-2836. (Elsevier B.V.)

    The thyroid hormone receptor (TR) D-domain links the ligand-binding domain (LBD, EF-domain) to the DNA-binding domain (DBD, C-domain), but its structure, and even its existence as a functional unit, are controversial. The D domain is poorly conserved throughout the nuclear receptor family and was originally proposed to comprise an unfolded hinge that facilitates rotation between the LBD and the DBD. Previous TR LBD structures, however, have indicated that the true unstructured region is three to six amino acid residues long and that the D-domain N terminus folds into a short amphipathic α-helix (H0) contiguous with the DBD and that the C terminus of the D-domain comprises H1 and H2 of the LBD. Here, we solve structures of TR-LBDs in different crystal forms and show that the N terminus of the TRα D-domain can adopt two structures; it can either fold into an amphipathic helix that resembles TRβ H0 or form an unstructured loop. H0 formation requires contacts with the AF-2 coactivator-binding groove of the neighboring TR LBD, which binds H0 sequences that resemble coactivator LXXLL motifs. Structural anal. of a liganded TR LBD with small angle x-ray scattering (SAXS) suggests that AF-2/H0 interactions mediate dimerization of this protein in soln. We propose that the TR D-domain has the potential to form functionally important extensions of the DBD and LBD or unfold to permit TRs to adapt to different DNA response elements. We also show that mutations of the D domain LXXLL-like motif indeed selectively inhibit TR interactions with an inverted palindromic response element (F2) in vitro and TR activity at this response element in cell-based transfection expts.

    >> More from SciFinder ^®

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xms1anurk%253D&md5=eba4708c3578389a868a8e9f47240cee

    
80. 80

    Dow, R. L.; Schneider, S. R.; Paight, E. S.; Hank, R. F.; Chiang, P.; Cornelius, P.; Lee, E.; Newsome, W. P.; Swick, A. G.; Spitzer, J.; Hargrove, D. M.; Patterson, T. A.; Pandit, J.; Chrunyk, B. A.; LeMotte, P. K.; Danley, D. E.; Rosner, M. H.; Ammirati, M. J.; Simons, S. P.; Schulte, G. K.; Tate, B. F.; DaSilva-Jardine, P. Discovery of a Novel Series of 6-Azauracil-Based Thyroid Hormone Receptor Ligands: Potent, TR Beta Subtype-Selective Thyromimetics. Bioorg. Med. Chem. Lett. 2003, 13, 379– 382,  DOI: 10.1016/S0960-894X(02)00947-2

    [Crossref], [PubMed], [CAS], Google Scholar

    80

    Discovery of a novel series of 6-azauracil-based thyroid hormone receptor ligands: potent, TRβ subtype-selective thyromimetics

    Dow, Robert L.; Schneider, Steven R.; Paight, Ernest S.; Hank, Richard F.; Chiang, Phoebe; Cornelius, Peter; Lee, Eunsun; Newsome, William P.; Swick, Andrew G.; Spitzer, Josephine; Hargrove, Diane M.; Patterson, Terrell A.; Pandit, Jayvardhan; Chrunyk, Boris A.; LeMotte, Peter K.; Danley, Dennis E.; Rosner, Michele H.; Ammirati, Mark J.; Simons, Samuel P.; Schulte, Gayle K.; Tate, Bonnie F.; DaSilva-Jardine, Paul

    Bioorganic & Medicinal Chemistry Letters (2003), 13 (3), 379-382CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science Ltd.)

    In this communication, we wish to describe the discovery of a novel series of 6-azauracil-based thyromimetics that possess up to 100-fold selectivities for binding and functional activation of the β1-isoform of the thyroid receptor family. Structure-activity relationship studies on the 3,5- and 3'-positions provided compds. with enhanced TRβ affinity and selectivity. Key binding interactions between the 6-azauracil moiety and the receptor have been detd. through of X-ray crystallog. anal.

    >> More from SciFinder ^®

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXptFagtA%253D%253D&md5=5af36444ade86b9670484844bb53500c

    
81. 81

    Grover, G. J.; Kelly, J.; Malm, J. Thyroid Hormone Receptor Subtype-Β-Selective Agonists as Potential Treatments for Metabolic Syndrome. Future Lipidol. 2007, 2, 641– 649,  DOI: 10.2217/17460875.2.6.641

    [Crossref], [CAS], Google Scholar

    81

    Thyroid hormone receptor subtype-β-selective agonists as potential treatments for metabolic syndrome

    Grover, Gary J.; Kelly, Jane; Malm, Johan

    Future Lipidology (2007), 2 (6), 641-649CODEN: FLUIBL; ISSN:1746-0875. (Future Medicine Ltd.)

    A review. Thyroid hormones are of interest because of their ability to reduce serum cholesterol and triglycerides and their ability to reduce adiposity. Unfortunately, naturally occurring thyroid hormones, such as T3 (thyroid hormone) or T4 (thyroxine), cannot be used to treat obesity or hyperlipidemia in euthyroid subjects owing to cardiovascular complications. The two primary thyroid hormone receptor (TR) subtypes, TRα and TRβ, are ubiquitously expressed, with TRα predominance in heart, bone and brain and TRβ predominance in the liver and pituitary. This selective expression and perhaps selective TR function makes TRβ agonists potentially useful for treating obesity and hyperlipidemia without cardiac effects. TRβ-selective activation shows promise as there is a therapeutic window in which cholesterol is lowered and metabolic rate is increased without cardiac acceleration. This was shown in TRα-/- mice and for the TRβ-selective agonists GC-1 and KB-141. This should translate into antiobesity, lipid-lowering and potentially antidiabetic effects for TRβ agonists.

    >> More from SciFinder ^®

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhtlKltb3I&md5=2881515b19899f3c435cc0fe9fa8653a

    
82. 82

    Sinha, R. A.; Singh, B. K.; Yen, P. M. Direct Effects of Thyroid Hormones on Hepatic Lipid Metabolism. Nat. Rev. Endocrinol. 2018, 14, 259– 269,  DOI: 10.1038/nrendo.2018.10

    [Crossref], [PubMed], [CAS], Google Scholar

    82

    Direct effects of thyroid hormones on hepatic lipid metabolism

    Sinha, Rohit A.; Singh, Brijesh K.; Yen, Paul M.

    Nature Reviews Endocrinology (2018), 14 (5), 259-269CODEN: NREABD; ISSN:1759-5029. (Nature Research)

    It has been known for a long time that thyroid hormones have prominent effects on hepatic fatty acid and cholesterol synthesis and metab. Indeed, hypothyroidism has been assocd. with increased serum levels of triglycerides and cholesterol as well as non-alc. fatty liver disease (NAFLD). Advances in areas such as cell imaging, autophagy and metabolomics have generated a more detailed and comprehensive picture of thyroid-hormone-mediated regulation of hepatic lipid metab. at the mol. level. In this Review, we describe and summarize the key features of direct thyroid hormone regulation of lipogenesis, fatty acid β-oxidn., cholesterol synthesis and the reverse cholesterol transport pathway in normal and altered thyroid hormone states. Thyroid hormone mediates these effects at the transcriptional and post-translational levels and via autophagy. Given these potentially beneficial effects on lipid metab., it is possible that thyroid hormone analogs and/or mimetics might be useful for the treatment of metabolic diseases involving the liver, such as hypercholesterolemia and NAFLD.

    >> More from SciFinder ^®

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXjtFOht7o%253D&md5=433b9ab213ee24ba5162848aad3dbf9a

    
83. 83

    Kelly, M. J.; Pietranico-Cole, S.; Larigan, J. D.; Haynes, N. E.; Reynolds, C. H.; Scott, N.; Vermeulen, J.; Dvorozniak, M.; Conde-Knape, K.; Huang, K. S.; So, S. S.; Thakkar, K.; Qian, Y.; Banner, B.; Mennona, F.; Danzi, S.; Klein, I.; Taub, R.; Tilley, J. Discovery of 2-[3,5-Dichloro-4-(5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yloxy)phenyl]-3,5-dioxo-2,3,4,5-tetrahydro[1,2,4]triazine-6-carbonitrile (MGL-3196), a Highly Selective Thyroid Hormone Receptor Beta Agonist in Clinical Trials for the Treatment of Dyslipidemia. J. Med. Chem. 2014, 57, 3912– 3923,  DOI: 10.1021/jm4019299

    [ACS Full Text ], [CAS], Google Scholar

    83

    Discovery of 2-[3,5-Dichloro-4-(5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yloxy)phenyl]-3,5-dioxo-2,3,4,5-tetrahydro[1,2,4]triazine-6-carbonitrile (MGL-3196), a Highly Selective Thyroid Hormone Receptor β Agonist in Clinical Trials for the Treatment of Dyslipidemia

    Kelly, Martha J.; Pietranico-Cole, Sherrie; Larigan, J. Douglas; Haynes, Nancy-Ellen; Reynolds, Charles H.; Scott, Nathan; Vermeulen, John; Dvorozniak, Mark; Conde-Knape, Karin; Huang, Kuo-Sen; So, Sung-Sau; Thakkar, Kshitij; Qian, Yimin; Banner, Bruce; Mennona, Frank; Danzi, Sara; Klein, Irwin; Taub, Rebecca; Tilley, Jefferson

    Journal of Medicinal Chemistry (2014), 57 (10), 3912-3923CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

    The beneficial effects of thyroid hormone (TH) on lipid levels are primarily due to its action at the thyroid hormone receptor β (THR-β) in the liver, while adverse effects, including cardiac effects, are mediated by thyroid hormone receptor α (THR-α). A pyridazinone series has been identified that is significantly more THR-β selective than earlier analogs. Optimization of this series by the addn. of a cyanoazauracil substituent improved both the potency and selectivity and led to MGL-3196 (53), which is 28-fold selective for THR-β over THR-α in a functional assay. Compd. 53 showed outstanding safety in a rat heart model and was efficacious in a preclin. model at doses that showed no impact on the central thyroid axis. In reported studies in healthy volunteers, 53 exhibited an excellent safety profile and decreased LDL cholesterol (LDL-C) and triglycerides (TG) at once daily oral doses of 50 mg or higher given for 2 wk.

    >> More from SciFinder ^®

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXlsl2ktr8%253D&md5=d6c265da87c2caa7ba260deee49cc926

    
84. 84

    Chiellini, G.; Apriletti, J. W.; Yoshihara, H. A.; Baxter, J. D.; Ribeiro, R. C.; Scanlan, T. S. A High-Affinity Subtype-Selective Agonist Ligand for the Thyroid Hormone Receptor. Chem. Biol. 1998, 5, 299– 306,  DOI: 10.1016/S1074-5521(98)90168-5

    [Crossref], [PubMed], [CAS], Google Scholar

    84

    A high-affinity subtype-selective agonist ligand for the thyroid hormone receptor

    Chiellini, Grazia; Apriletti, James W.; Yoshihara, Hikari Al; Baxter, John D.; Ribeiro, Ralff C. J.; Scanlan, Thomas S.

    Chemistry & Biology (1998), 5 (6), 299-306CODEN: CBOLE2; ISSN:1074-5521. (Current Biology Ltd.)

    Thyroid hormones regulate many different physiol. processes in different tissues in vertebrates. Most of the actions of thyroid hormones are mediated by the thyroid hormone receptor (TR), which is a member of the nuclear receptor superfamily of ligand-activated transcription regulators. There are two different genes that encode two different TRs, TRα and TRβ, and these two TRs are often co-expressed at different levels in different tissues. Most thyroid hormones do not discriminate between the two TRs and bind both with similar affinities. The authors have designed and synthesized a thyroid hormone analog that has high affinity for the TRs and is selective in both binding and activation functions for TRβ over TRα. The compd., GC-1, was initially designed to solve synthetic problems that limit thyroid hormone analog prepn., and contains several structural changes with respect to the natural hormone 3,5,3'-triiodo-L-thyronine (T3). These changes include replacement of the three iodines with Me and iso-Pr groups, replacement of the biaryl ether linkage with a methylene linkage, and replacement of the amino-acid sidechain with an oxyacetic-acid sidechain. The result of this study show that GC-1 is a member of a new class of thyromimetic compds. that are more synthetically accessible than traditional thyromimetics and have potentially useful receptor binding and activation properties. The TRβ selectivity of GC-1 is particularly interesting and suggests that GC-1 might be a useful in vivo probe for studying the physiol. roles of the different thyroid hormone receptor isoforms.

    >> More from SciFinder ^®

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXktlGgs7g%253D&md5=9b167bfa39eb31cbd424a6a2e8eadd4b

    
85. 85

    Grover, G. J.; Mellstrom, K.; Ye, L.; Malm, J.; Li, Y. L.; Bladh, L. G.; Sleph, P. G.; Smith, M. A.; George, R.; Vennstrom, B.; Mookhtiar, K.; Horvath, R.; Speelman, J.; Egan, D.; Baxter, J. D. Selective Thyroid Hormone Receptor-Beta Activation: A Strategy for Reduction of Weight, Cholesterol, and Lipoprotein (a) with Reduced Cardiovascular Liability. Proc. Natl. Acad. Sci. U. S. A. 2003, 100, 10067– 10072,  DOI: 10.1073/pnas.1633737100

    [Crossref], [PubMed], [CAS], Google Scholar

    85

    Selective thyroid hormone receptor-β activation: A strategy for reduction of weight, cholesterol, and lipoprotein (a) with reduced cardiovascular liability

    Grover, Gary J.; Mellstroem, Karin; Ye, Liu; Malm, Johan; Li, Yi-Lin; Bladh, Lars-Goeran; Sleph, Paul G.; Smith, Mark A.; George, Rocco; Vennstroem, Bjoern; Mookhtiar, Kasim; Horvath, Ryan; Speelman, Jessica; Egan, Donald; Baxter, John D.

    Proceedings of the National Academy of Sciences of the United States of America (2003), 100 (17), 10067-10072CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)

    Few treatments for obesity exist and, whereas efficacious therapeutics for hyperlipidemia are available, further improvements are desirable. Thyroid hormone receptors (TRs) regulate both body wt. and cholesterol levels. However, thyroid hormones also have deleterious effects, particularly on the heart. The TRβ subtype is involved in cholesterol lowering and possibly elevating metabolic rate, whereas TRα appears to be more important for control of heart rate (HR). In the current studies, we examd. the effect of TRβ activation on metabolic rate and HR with either TRα1-/- mice or the selective TRβ agonist KB-141 in mice, rats, and monkeys. 3,5,3'-Triiodo-L-thyronine (T3) had a greater effect on increasing HR in WT than in TRα-/- mice (ED15 values of 34 and 469 nmol/kg/day, resp.). T3 increased metabolic rate [whole body oxygen consumption (MVo2)] in both WT and TRα-/- mice, but the effect in the TRα1-/- mice at the highest dose was half that of the WT mice. Thus, stimulation of MVo2 is likely due to both TRα and -β. T3 had equiv. potency for cholesterol redn. in WT and TRα-/- mice. KB-141 increased MVo2 with selectivities of 16.5- and 11.2-fold vs. HR in WT and TRα1-/- mice, resp. KB-141 also increased MVo2 with a 10-fold selectivity and lowered cholesterol with a 27-fold selectivity vs. HR in rats. In primates, KB-141 caused significant cholesterol, lipoprotein (a), and body-wt. redn. (up to 7% after 1 wk) with no effect on HR. TRβ-selective agonists may constitute a previously uncharacterized class of drugs to treat obesity, hypercholesterolemia, and elevated lipoprotein (a).

    >> More from SciFinder ^®

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXmvVeis7s%253D&md5=ece142766dd43053c280c73ca417a6fb

    
86. 86

    Joharapurkar, A. A.; Dhote, V. V.; Jain, M. R. Selective Thyromimetics Using Receptor and Tissue Selectivity Approaches: Prospects for Dyslipidemia. J. Med. Chem. 2012, 55, 5649– 5675,  DOI: 10.1021/jm2004706

    [ACS Full Text ], [CAS], Google Scholar

    86

    Selective Thyromimetics Using Receptor and Tissue Selectivity Approaches: Prospects for Dyslipidemia

    Joharapurkar, Amit A.; Dhote, Vipin V.; Jain, Mukul R.

    Journal of Medicinal Chemistry (2012), 55 (12), 5649-5675CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

    A review. Selective Thyromimetics Using Receptor and Tissue Selectivity Approaches: Prospects for Dyslipidemia.

    >> More from SciFinder ^®

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XlslGqs7w%253D&md5=96112d59cf060926e0c529bb472b74bd

    
87. 87

    Taub, R.; Chiang, E.; Chabot-Blanchet, M.; Kelly, M. J.; Reeves, R. A.; Guertin, M. C.; Tardif, J. C. Lipid Lowering in Healthy Volunteers Treated with Multiple Doses of MGL-3196, a Liver-Targeted Thyroid Hormone Receptor-Beta Agonist. Atherosclerosis 2013, 230, 373– 380,  DOI: 10.1016/j.atherosclerosis.2013.07.056

    [Crossref], [PubMed], [CAS], Google Scholar

    87

    Lipid lowering in healthy volunteers treated with multiple doses of MGL-3196, a liver-targeted thyroid hormone receptor-β agonist

    Taub, Rebecca; Chiang, Edward; Chabot-Blanchet, Malorie; Kelly, Martha J.; Reeves, Richard A.; Guertin, Marie-Claude; Tardif, Jean-Claude

    Atherosclerosis (Amsterdam, Netherlands) (2013), 230 (2), 373-380CODEN: ATHSBL; ISSN:0021-9150. (Elsevier B.V.)

    MGL-3196 is an oral, liver-targeted selective agonist for the thyroid hormone receptor-β (THR-β) that is being developed for the treatment of dyslipidemia. The safety profile and tolerability of THR-β agonist MGL-3196 was assessed in first-in humans studies, including a single ascending dose study (NCT01367873) in which MGL-3196 appeared safe at all doses tested. A two-week multiple dose study was conducted at doses of 5, 20, 50, 80, 100, and 200 mg per day in healthy subjects with mildly elevated low d. lipoprotein (LDL) cholesterol (>110 mg/dL) (NCT01519531). MGL-3196 was well-tolerated at all doses with no dose-related adverse events or liver enzyme, ECG or vital-sign changes. At the highest dose, there was a reversible redn. of ∼20% in the level of pro-hormone, free thyroxine (free T4) that was significantly different from placebo (p < 0.0001) that may be explained by increased hepatic metab. of T4. There was no change in TSH (TSH) or triiodothyronine (free T3) or other evidence of central thyroid axis dysfunction at any dose. Doses ranging from 50 to 200 mg demonstrated highly statistically significant redns. relative to placebo of up to: 30% for LDL cholesterol (range, p = 0.05-<0.0001); 28% for non- high d. lipoprotein (HDL) cholesterol (range, p = 0.027-0.0001); 24% for Apolipoprotein B (range, p = 0.008-0.0004), and statistical trends of up to 60% redn. in triglycerides (TG) (range, p = 0.13-0.016). The near maximal lipid effects were obsd. at a dose of 80 mg daily. In summary, in a two-week study in healthy volunteers with mild LDL cholesterol elevation, MGL-3196 appeared safe, was well-tolerated and showed a beneficial effect on lipid parameters.

    >> More from SciFinder ^®

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsFemsL%252FI&md5=2366582e548b76433b52c9d2b5d9f4eb

    
88. 88

    Harrison, S.; Guy, C.; Bashir, M.; Frias, J.; Alkhouri, N.; Baum, S.; Taub, R.; Moylan, C.; Bansal, M.; Neuschwander-Tetri, B. A.; Moussa, S. In a Placebo-Controlled 36-Week Phase 2 Trial, Treatment with MGL-3196 Compared with Placebo Results in Significant Reductions in Hepatic Fat (MRI-PDFF), Liver Enzymes, Fibrosis Biomarkers, Atherogenic Lipids, and Improvement in Nash on Serial Liver Biopsy. Presented at the American Association for the Study of Liver Diseases, San Francisco, USA, November 9–13, 2018, ABS 14.

    Google Scholar

    There is no corresponding record for this reference.

    
89. 89

    Harrison, S. A.; Bashir, M. R.; Guy, C. D.; Zhou, R.; Moylan, C. A.; Frias, J. P.; Alkhouri, N.; Bansal, M. B.; Baum, S.; Neuschwander-Tetri, B. A.; Taub, R.; Moussa, S. E. Resmetirom (MGL-3196) for the treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet 2019, 394, 2012– 2024,  DOI: 10.1016/S0140-6736(19)32517-6

    [Crossref], [PubMed], [CAS], Google Scholar

    89

    Resmetirom (MGL-3196) for the treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial

    Harrison, Stephen A.; Bashir, Mustafa R.; Guy, Cynthia D.; Zhou, Rong; Moylan, Cynthia A.; Frias, Juan P.; Alkhouri, Naim; Bansal, Meena B.; Baum, Seth; Neuschwander-Tetri, Brent A.; Taub, Rebecca; Moussa, Sam E.

    Lancet (2019), 394 (10213), 2012-2024CODEN: LANCAO; ISSN:0140-6736. (Elsevier Ltd.)

    Non-alc. steatohepatitis (NASH) is characterised by hepatic steatosis, inflammation, hepatocellular injury, and progressive liver fibrosis. Resmetirom (MGL-3196) is a liver-directed, orally active, selective thyroid hormone receptor-β agonist designed to improve NASH by increasing hepatic fat metab. and reducing lipotoxicity. We aimed to assess the safety and efficacy of resmetirom in patients with NASH. MGL-3196-05 was a 36-wk randomised, double-blind, placebo-controlled study at 25 centers in the USA. Adults with biopsy confirmed NASH (fibrosis stages 1-3) and hepatic fat fraction of at least 10% at baseline when assessed by MRI-proton d. fat fraction (MRI-PDFF) were eligible. Patients were randomly assigned 2:1 by a computer-based system to receive resmetirom 80 mg or matching placebo, orally once a day. Serial hepatic fat measurements were obtained at weeks 12 and 36, and a second liver biopsy was obtained at week 36. The primary endpoint was relative change in MRI-PDFF assessed hepatic fat compared with placebo at week 12 in patients who had both a baseline and week 12 MRI-PDFF. This trial is registered with ClinicalTrials.gov, no. NCT02912260.348 patients were screened and 84 were randomly assigned to resmetirom and 41 to placebo at 18 sites in the USA. Resmetirom-treated patients (n=78) showed a relative redn. of hepatic fat compared with placebo (n=38) at week 12 (-32·9% resmetirom vs -10·4% placebo; least squares mean difference -22·5%, 95% CI -32·9 to -12·2; p&lt;0·0001) and week 36 (-37·3% resmetirom [n=74] vs -8·5 placebo [n=34]; -28·8%, -42·0 to -15·7; p&lt;0·0001). Adverse events were mostly mild or moderate and were balanced between groups, except for a higher incidence of transient mild diarrhoea and nausea with resmetirom. Resmetirom treatment resulted in significant redn. in hepatic fat after 12 wk and 36 wk of treatment in patients with NASH. Further studies of resmetirom will allow assessment of safety and effectiveness of resmetirom in a larger no. of patients with NASH with the possibility of documenting assocns. between histol. effects and changes in non-invasive markers and imaging.Madrigal Pharmaceuticals.

    >> More from SciFinder ^®

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitFels73L&md5=3773b5921a9a5e88959646a73486efbf

    
90. 90

    Boyer, S. H.; Jiang, H.; Jacintho, J. D.; Reddy, M. V.; Li, H.; Li, W.; Godwin, J. L.; Schulz, W. G.; Cable, E. E.; Hou, J.; Wu, R.; Fujitaki, J. M.; Hecker, S. J.; Erion, M. D. Synthesis and Biological Evaluation of a Series of Liver-Selective Phosphonic Acid Thyroid Hormone Receptor Agonists and their Prodrugs. J. Med. Chem. 2008, 51, 7075– 7093,  DOI: 10.1021/jm800824d

    [ACS Full Text ], [CAS], Google Scholar

    90

    Synthesis and Biological Evaluation of a Series of Liver-Selective Phosphonic Acid Thyroid Hormone Receptor Agonists and Their Prodrugs

    Boyer, Serge H.; Jiang, Hongjian; Jacintho, Jason D.; Reddy, Mali Venkat; Li, Haiqing; Li, Wenyu; Godwin, Jennifer L.; Schulz, William G.; Cable, Edward E.; Hou, Jinzhao; Wu, Rongrong; Fujitaki, James M.; Hecker, Scott J.; Erion, Mark D.

    Journal of Medicinal Chemistry (2008), 51 (22), 7075-7093CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

    Phosphonic acid (PA) thyroid hormone receptor (TR) agonists were synthesized to exploit the poor distribution of PA-based drugs to extrahepatic tissues and thereby to improve the therapeutic index. Nine PAs showed excellent TR binding affinities (TRβ1, Ki < 10 nM), and most of them demonstrated significant cholesterol lowering effects in a cholesterol-fed rat (CFR) model. Unlike the corresponding carboxylic acid analog and T3, PA 22c demonstrated liver-selective effects by inducing maximal mitochondrial glycerol-3-phosphate dehydrogenase activity in rat liver while having no effect in the heart. Because of the low oral bioavailability of PA 22c, a series of prodrugs was synthesized and screened for oral efficacy in the CFR assay. The liver-activated cyclic 1-(3-chlorophenyl)-1,3-propanyl prodrug (MB07811) showed potent lipid lowering activity in the CFR (ED50 0.4 mg/kg, po) and good oral bioavailability (40%, rat) and was selected for development for the treatment of hypercholesterolemia.

    >> More from SciFinder ^®

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhtlWqu7jK&md5=1a93543ad41af90677de8aec15a6ab9a

    
91. 91

    Erion, M. D.; Cable, E. E.; Ito, B. R.; Jiang, H.; Fujitaki, J. M.; Finn, P. D.; Zhang, B. H.; Hou, J.; Boyer, S. H.; van Poelje, P. D.; Linemeyer, D. L. Targeting Thyroid Hormone Receptor-Beta Agonists to the Liver Reduces Cholesterol and Triglycerides and Improves the Therapeutic Index. Proc. Natl. Acad. Sci. U. S. A. 2007, 104, 15490– 15495,  DOI: 10.1073/pnas.0702759104

    [Crossref], [PubMed], [CAS], Google Scholar

    91

    Targeting thyroid hormone receptor-β agonists to the liver reduces cholesterol and triglycerides and improves the therapeutic index

    Erion, Mark D.; Cable, Edward E.; Ito, Bruce R.; Jiang, Hongjian; Fujitaki, James M.; Finn, Patricia D.; Zhang, Bao-Hong; Hou, Jinzhao; Boyer, Serge H.; van Poelje, Paul D.; Linemeyer, David L.

    Proceedings of the National Academy of Sciences of the United States of America (2007), 104 (39), 15490-15495CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)

    Despite efforts spanning four decades, the therapeutic potential of thyroid hormone receptor (TR) agonists as lipid-lowering and anti-obesity agents remains largely unexplored in humans because of dose-limiting cardiac effects and effects on the thyroid hormone axis (THA), muscle metab., and bone turnover. TR agonists selective for the TRβ isoform exhibit modest cardiac sparing in rodents and primates but are unable to lower lipids without inducing TRβ-mediated suppression of the THA. Herein, we describe a cytochrome P 450-activated prodrug of a phosphonate-contg. TR agonist that exhibits increased TR activation in the liver relative to extrahepatic tissues and an improved therapeutic index. Pharmacokinetic studies in rats demonstrated that the prodrug (2R,4S)-4-(3-chlorophenyl)-2-[(3,5-dimethyl-4-(4'-hydroxy-3'-isopropylbenzyl)phenoxy)methyl]-2-oxido-[1,3,2]-dioxaphosphonane (MB07811) undergoes first-pass hepatic extn. and that cleavage of the prodrug generates the neg. charged TR agonist (3,5-dimethyl-4(4'-hydroxy-3'-isopropylbenzyl)phenoxy)methylphosphonic acid (MB07344), which distributes poorly into most tissues and is rapidly eliminated in the bile. Enhanced liver targeting was further demonstrated by comparing the effects of MB07811 with 3,5,3'-triiodo-L-thyronine (T3) and a non-liver-targeted TR agonist, 3,5-dichloro-4-(4-hydroxy-3-isopropylphenoxy)phenylacetic acid (KB-141) on the expression of TR agonist-responsive genes in the liver and six extrahepatic tissues. The pharmacol. effects of liver targeting were evident in the normal rat, where MB07811 exhibited increased cardiac sparing, and in the diet-induced obese mouse, where, unlike KB-141, MB07811 reduced cholesterol and both serum and hepatic triglycerides at doses devoid of effects on body wt., glycemia, and the THA. These results indicate that targeting TR agonists to the liver has the potential to lower both cholesterol and triglyceride levels with an acceptable safety profile.

    >> More from SciFinder ^®

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhtFajs7jF&md5=d789096c0be6d131ee5b8323d4cd87e3

    
92. 92

    Fujitaki, J. M.; Cable, E. E.; Ito, B. R.; Zhang, B. H.; Hou, J.; Yang, C.; Bullough, D. A.; Ferrero, J. L.; van Poelje, P. D.; Linemeyer, D. L.; Erion, M. D. Preclinical Pharmacokinetics of a Hepdirect Prodrug of a Novel Phosphonate-Containing Thyroid Hormone Receptor Agonist. Drug Metab. Dispos. 2008, 36, 2393– 2403,  DOI: 10.1124/dmd.108.021642

    [Crossref], [PubMed], [CAS], Google Scholar

    92

    Preclinical pharmacokinetics of a HepDirect prodrug of a novel phosphonate-containing thyroid hormone receptor agonist

    Fujitaki, James M.; Cable, Edward E.; Ito, Bruce R.; Zhang, Bao-Hong; Hou, Jinzhao; Yang, Chun; Bullough, David A.; Ferrero, James L.; van Poelje, Paul D.; Linemeyer, David L.; Erion, Mark D.

    Drug Metabolism and Disposition (2008), 36 (11), 2393-2403CODEN: DMDSAI; ISSN:0090-9556. (American Society for Pharmacology and Experimental Therapeutics)

    The prodrug [(2R,4S)-4-(3-chlorophenyl)-2-[(3,5-dimethyl-4-(4'-hydroxy-3'-isopropylbenzyl)phenoxy)methyl]-2-oxido-[1,3,2]-dioxaphosphonane (MB07811)] of a novel phosphonate-contg. thyroid hormone receptor agonist [3,5-dimethyl-4-(4'-hydroxy-3'-isopropylbenzyl)phenoxylmethylphosphonic acid (MB07344)] is the first application of the HepDirect liver-targeting approach to a non-nucleotide agent. The disposition of MB07811 was characterized in rat, dog, and monkey to assess its liver specificity, which is essential in limiting the extrahepatic side effects assocd. with this class of lipid-lowering agents. MB07811 was converted to MB07344 in liver microsomes from all species tested (CLint 1.23-145.4 μl/min/mg). The plasma clearance and vol. of distribution of MB07811 matched or exceeded 1 l/h/kg and 3 l/kg, resp. Although absorption of prodrug was good, its abs. oral bioavailability as measured systemically was low (3-10%), an indication of an extensive hepatic first-pass effect. This effect was confirmed by comparison of systemic exposure levels of MB07811 after portal and jugular vein administration to rats, which demonstrated a hepatic extn. ratio of >0.6 with liver CYP3A-mediated conversion to MB07344 being a major component. The main route of elimination of MB07811 and MB07344 was biliary, with no evidence for enterohepatic recirculation of MB07344. Similar metabolic profiles of MB07811 were obtained in liver microsomes across the species tested. Tissue distribution and whole body autoradiog. confirmed that the liver is the major target organ of MB07811 and that conversion to MB07344 was high in the liver relative to that in other tissues. Hepatic first-pass extn. and metab. of MB07811, coupled with possible selective distribution of MB07811-derived MB07344, led to a high degree of liver targeting of MB07344.

    >> More from SciFinder ^®

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhtlWiu7%252FO&md5=3d8260bfb95696c6145d05ddc52fa36a

    
93. 93

    Lombda, R.; Neutel, J.; Bernard, D.; Severance, R.; Mohseni, R.; Dao, M.; Saini, S.; Margaritescu, C.; Homer, K.; Tran, B.; Mancini, M.; Masume, H.; Lian, B. VK2809, a Novel Liver-Directed Thyroid Receptor Beta Agonist, Significantly Reduces Liver Fat in Patients with Non-Alcoholic Fatty Liver Disease: A Phase 2 Randomized, Placebo-Controlled Trial. Presented at the American Association for the Study of Liver Diseases, San Francisco, USA, November 9–13, 2018; LB-4.

    Google Scholar

    There is no corresponding record for this reference.

    
94. 94

    Babaknejad, N.; Nayeri, H.; Hemmati, R.; Bahrami, S.; Esmaillzadeh, A. An Overview of FGF19 and FGF21: The Therapeutic Role in the Treatment of the Metabolic Disorders and Obesity. Horm. Metab. Res. 2018, 50, 441– 452,  DOI: 10.1055/a-0623-2909

    [Crossref], [PubMed], [CAS], Google Scholar

    94

    An Overview of FGF19 and FGF21: The Therapeutic Role in the Treatment of the Metabolic Disorders and Obesity

    Babaknejad, Nasim; Nayeri, Hashem; Hemmati, Roohullah; Bahrami, Somaye; Esmaillzadeh, Ahmad

    Hormone and Metabolic Research (2018), 50 (6), 441-452CODEN: HMMRA2; ISSN:0018-5043. (Georg Thieme Verlag)

    Fibroblast growth factors (FGFs) are responsible for the regulation of a wide range of biol. functions, among which cellular proliferation, survival, migration, and differentiation could be pointed out. FGF19 controls the enterohepatic bile acid/cholesterol system, and FGF21 modulates fatty acid/glucose metab. Obesity, type 2 diabetes, coronary artery disease, and cancer, all can alter FGF21 circulating concns. In contrast to FGF21, metabolic diseases exhibit reduced serum FGF19 levels. Accordingly, FGF19 and FGF21 play important roles in regulating glucose and lipid metab. Hence, we present here a timely review on the relationship between FGF19/21 and metabolic diseases, esp. obesity, and their probable role in development and treatment of obesity seems necessary.

    >> More from SciFinder ^®

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtFSmurnL&md5=b86544dc4ab2fd78e40c55cdd8bc8452

    
95. 95

    Walters, J. R.; Tasleem, A. M.; Omer, O. S.; Brydon, W. G.; Dew, T.; le Roux, C. W. A New Mechanism for Bile Acid Diarrhea: Defective Feedback Inhibition of Bile Acid Biosynthesis. Clin. Gastroenterol. Hepatol. 2009, 7, 1189– 1194,  DOI: 10.1016/j.cgh.2009.04.024

    [Crossref], [PubMed], [CAS], Google Scholar

    95

    A new mechanism for bile acid diarrhea: defective feedback inhibition of bile acid biosynthesis

    Walters, Julian R. F.; Tasleem, Ali M.; Omer, Omer S.; Brydon, W. Gordon; Dew, Tracy; Le Roux, Carel W.

    Clinical Gastroenterology and Hepatology (2009), 7 (11), 1189-1194CODEN: CGHLAW; ISSN:1542-3565. (Elsevier Inc.)

    BACKGROUND & AIMS: Primary (idiopathic) bile acid malabsorption (BAM) is a common, yet underrecognized, chronic diarrheal syndrome. Diagnosis is difficult without selenium homocholic acid taurine (SeHCAT) testing. The diarrhea results from excess colonic bile acids, but the pathogenesis is unclear. Fibroblast growth factor 19 (FGF19), produced in the ileum in response to bile acid absorption, regulates hepatic bile acid synthesis. We proposed that FGF19 is involved in bile acid diarrhea and measured its levels in patients with BAM. METHODS: Blood was collected from fasting patients with chronic diarrhea; BAM was diagnosed by SeHCAT. Serum FGF19 was measured by ELISA. Serum 7α-hydroxy-4-cholesten-3-one (C4) was detd. using high-performance liq. chromatog., to quantify bile acid synthesis. Data were compared between patients and subjects without diarrhea (controls). Samples were taken repeatedly after meals from several subjects. RESULTS: The median C4 level was significantly higher in patients with primary BAM than in controls (51 vs 18 ng/mL; P < .0001). The median FGF19 level was significantly lower in patients with BAM (120 vs 231 pg/mL; P < .0005). There was a significant inverse relationship between FGF19 and C4 levels (P < .0004). Low levels of FGF19 were also found in patients with postcholecystectomy and secondary bile acid diarrhea. Abnormal patterns of FGF19 levels were obsd. throughout the day in some patients with primary BAM. CONCLUSIONS: Patients with BAM have reduced serum FGF19 which may be useful in diagnosis. We propose a mechanism whereby impaired FGF19 feedback inhibition causes excessive bile acid synthesis that exceeds the normal capacity for ileal reabsorption, producing bile acid diarrhea.

    >> More from SciFinder ^®

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXlsFOisg%253D%253D&md5=b8d0b08083108e54238bc97c80be9f4d

    
96. 96

    Bhatnagar, S.; Damron, H. A.; Hillgartner, F. B. Fibroblast Growth Factor-19, A Novel Factor that Inhibits Hepatic Fatty Acid Synthesis. J. Biol. Chem. 2009, 284, 10023– 10033,  DOI: 10.1074/jbc.M808818200

    [Crossref], [PubMed], [CAS], Google Scholar

    96

    Fibroblast Growth Factor-19, a novel factor that inhibits hepatic fatty acid synthesis

    Bhatnagar, Sushant; Damron, Holly A.; Hillgartner, F. Bradley

    Journal of Biological Chemistry (2009), 284 (15), 10023-10033CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)

    Previous studies have shown that administration of fibroblast growth factor-19 (FGF-19) reverses diabetes, hepatic steatosis, hyperlipidemia, and adipose accretion in animal models of obesity. To investigate the mechanism for this effect, we detd. whether FGF-19 modulated hepatic fatty acid synthesis, a key process controlling glucose tolerance and triacylglycerol accumulation in liver, blood, and adipose tissue. Incubating primary hepatocyte cultures with recombinant FGF-19 suppressed the ability of insulin to stimulate fatty acid synthesis. This effect was assocd. with a redn. in the expression of lipogenic enzymes. FGF-19 also suppressed the insulin-induced expression of sterol regulatory element-binding protein-1c (SREBP-1c), a key transcriptional activator of lipogenic genes. FGF-19 inhibition of lipogenic enzyme expression was not mediated by alterations in the activity of the insulin signal transduction pathway or changes in the activity of ERK, p38 MAPK, and AMP-activated protein kinase (AMPK). In contrast, FGF-19 increased the activity of STAT3, an inhibitor of SREBP-1c expression and decreased the expression of peroxisome proliferator-activated receptor-γ coactivator-1β (PGC-1β), an activator of SREBP-1c activity. FGF-19 also increased the expression of small heterodimer partner (SHP), a transcriptional repressor that inhibits lipogenic enzyme expression via a SREBP-1c-independent mechanism. Inhibition of SREBP-1c activity by changes in STAT3 and PGC-1β activity and inhibition of gene transcription by an elevation in SHP expression can explain the inhibition of lipogenesis caused by FGF-19. In summary, the inhibitory effect of FGF-19 on insulin activation of hepatic fatty acid synthesis constitutes a mechanism that would explain the beneficial effect of FGF-19 on metabolic syndrome.

    >> More from SciFinder ^®

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXjvFKlu7k%253D&md5=162385877409d91f33567de311d06fdc

    
97. 97

    Lin, B. C.; Desnoyers, L. R. FGF19 And Cancer. Adv. Exp. Med. Biol. 2012, 728, 183– 194,  DOI: 10.1007/978-1-4614-0887-1_12

    [Crossref], [PubMed], [CAS], Google Scholar

    97

    FGF19 and cancer

    Lin, Benjamin C.; Desnoyers, Luc R.

    Advances in Experimental Medicine and Biology (2012), 728 (Endocrine FGFs and Klothos), 183-194CODEN: AEMBAP; ISSN:0065-2598. (Springer)

    A review. Fibroblast growth factors (FGFs) and their cognate receptors, FGF receptors (FGFRs), play crit. roles in a variety of normal developmental and physiol. processes. Numerous reports support a role for deregulation of FGF-FGFR signaling, whether it is at the ligand and/or receptor level, in tumor development and progression. The FGF19-FGFR4 signaling axis has been implicated in the pathogenesis of several cancers, including hepatocellular carcinomas in mice and potentially in humans. This chapter focuses on recent progress in the understanding of the mol. mechanisms of FGF19 action and its potential involvement in cancer.

    >> More from SciFinder ^®

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xhtlynsb3K&md5=083026a28a3e9da69ca46d32347c44be

    
98. 98

    Tezze, C.; Romanello, V.; Sandri, M. FGF21 as Modulator of Metabolism in Health and Disease. Front. Physiol. 2019, 10, 419,  DOI: 10.3389/fphys.2019.00419

    [Crossref], [PubMed], [CAS], Google Scholar

    98

    FGF21 as Modulator of Metabolism in Health and Disease

    Tezze Caterina; Romanello Vanina; Sandri Marco; Tezze Caterina; Romanello Vanina; Sandri Marco; Sandri Marco; Sandri Marco

    Frontiers in physiology (2019), 10 (), 419 ISSN:1664-042X.

    Fibroblast growth factor 21 (FGF21) is a hormone that regulates important metabolic pathways. FGF21 is expressed in several metabolically active organs and interacts with different tissues. The FGF21 function is complicated and well debated due to its different sites of production and actions. Striated muscles are plastic tissues that undergo adaptive changes within their structural and functional properties in order to meet their different stresses, recently, they have been found to be an important source of FGF21. The FGF21 expression and secretion from skeletal muscles happen in both mouse and in humans during their different physiological and pathological conditions, including exercise and mitochondrial dysfunction. In this review, we will discuss the recent findings that identify FG21 as beneficial and/or detrimental cytokine interacting as an autocrine or endocrine in order to modulate cellular function, metabolism, and senescence.

    >> More from SciFinder ^®

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3M7is1Ghsw%253D%253D&md5=9ff76a19cadd8eeade85cc34f1f4da29

    
99. 99

    Zhou, M.; Yang, H.; Learned, R. M.; Tian, H.; Ling, L. Non-Cell-Autonomous Activation of IL-6/STAT3 Signaling Mediates FGF19-Driven Hepatocarcinogenesis. Nat. Commun. 2017, 8, 15433,  DOI: 10.1038/ncomms15433

    [Crossref], [PubMed], [CAS], Google Scholar

    99

    Non-cell-autonomous activation of IL-6/STAT3 signaling mediates FGF19-driven hepatocarcinogenesis

    Zhou, Mei; Yang, Hong; Learned, R. Marc; Tian, Hui; Ling, Lei

    Nature Communications (2017), 8 (), 15433CODEN: NCAOBW; ISSN:2041-1723. (Nature Publishing Group)

    Hepatocellular carcinoma (HCC), a primary malignancy of the liver, is the second leading cause of cancer mortality worldwide. Fibroblast Growth Factor 19 (FGF19) is one of the most frequently amplified genes in HCC patients. Moreover, mice expressing an FGF19 transgene have been shown to develop HCC. However, the downstream signalling pathways that mediate FGF19-dependent tumorigenesis remain to be deciphered. Here we show that FGF19 triggers a previously unsuspected, non-cell-autonomous program to activate STAT3 signalling in hepatocytes through IL-6 produced in the liver microenvironment. We show that the hepatocyte-specific deletion of Stat3, genetic ablation of Il6, treatment with a neutralizing anti-IL-6 antibody or administration of a small-mol. JAK inhibitor, abolishes FGF19-induced tumorigenesis, while the regulatory functions of FGF19 in bile acid, glucose and energy metab. remain intact. Collectively, these data reveal a key role for the IL-6/STAT3 axis in potentiating FGF19-driven HCC in mice, a finding which may have translational relevance in HCC pathogenesis.

    >> More from SciFinder ^®

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXnvFGgsro%253D&md5=57c08169f5c33505627938f5be7fed73

    
100. 100

     Zhou, M.; Wang, X.; Phung, V.; Lindhout, D. A.; Mondal, K.; Hsu, J. Y.; Yang, H.; Humphrey, M.; Ding, X.; Arora, T.; Learned, R. M.; DePaoli, A. M.; Tian, H.; Ling, L. Separating Tumorigenicity from Bile Acid Regulatory Activity for Endocrine Hormone FGF19. Cancer Res. 2014, 74, 3306– 3316,  DOI: 10.1158/0008-5472.CAN-14-0208

     [Crossref], [PubMed], [CAS], Google Scholar

     100

     Separating Tumorigenicity from Bile Acid Regulatory Activity for Endocrine Hormone FGF19

     Zhou, Mei; Wang, Xueyan; Phung, Van; Lindhout, Darrin A.; Mondal, Kalyani; Hsu, Jer-Yuan; Yang, Hong; Humphrey, Mark; Ding, Xunshan; Arora, Taruna; Learned, R. Marc; De Paoli, Alex M.; Tian, Hui; Ling, Lei

     Cancer Research (2014), 74 (12), 3306-3316CODEN: CNREA8; ISSN:0008-5472. (American Association for Cancer Research)

     Hepatocellular carcinoma (HCC), one of the leading causes of cancer-related death, develops from premalignant lesions in chronically damaged livers. Although it is well established that FGF19 acts through the receptor complex FGFR4-β-Klotho(KLB) to regulate bile acid metab., FGF19 is also implicated in the development of HCC. In humans, FGF19 is amplified in HCC and its expression is induced in the liver under cholestatic and cirrhotic conditions. In mice, ectopic overexpression of FGF19 drives HCC development in a process that requires FGFR4. In this study, we describe an engineered FGF19 (M70) that fully retains bile acid regulatory activity but does not promote HCC formation, demonstrating that regulating bile acid metab. is distinct and separable from tumor- promoting activity. Mechanistically, we show that FGF19 stimulates tumor progression by activating the STAT3 pathway, an activity eliminated by M70. Furthermore, M70 inhibits FGF19-dependent tumor growth in a rodent model. Our results suggest that selectively targeting the FGF19-FGFR4 pathway may offer a tractable approach to improve the treatment of chronic liver disease and cancer.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXps1Cmur4%253D&md5=68696507ee95978ae497a82b5c1aa7d3

     
101. 101

     Harrison, S. A.; Rossi, S. J.; Paredes, A. H.; Trotter, J. F.; Bashir, M. R.; Guy, C. D.; Banerjee, R.; Jaros, M. J.; Owers, S.; Baxter, B. A.; Ling, L.; DePaoli, A. M. NGM282 Improves Liver Fibrosis and Histology in 12 Weeks in Patients With Nonalcoholic Steatohepatitis. Hepatology 2019,  DOI: 10.1002/hep.30590

     [Crossref], Google Scholar

     There is no corresponding record for this reference.

     
102. 102

     Harrison, S. A.; Banerjee, R.; Trotter, J. F.; Paredes, A. H.; Army, B.; Jaros, M.; Ling, L.; DePaoli, A. 12 Weeks of NGM282 Therapy Produced Significant and Sustained Reduction in cT1 in Patients with Nonalcoholic Steatohepatitis. Presented at the American Association for the Study of Liver Diseases, Boston, USA, November 13–17, 2019, 1747.

     Google Scholar

     There is no corresponding record for this reference.

     
103. 103

     Harrison, S. A.; Rinella, M. E.; Abdelmalek, M. F.; Trotter, J. F.; Paredes, A. H.; Arnold, H. L.; Kugelmas, M.; Bashir, M. R.; Jaros, M. J.; Ling, L.; Rossi, S. J.; DePaoli, A. M.; Loomba, R. NGM282 for Treatment of Non-Alcoholic Steatohepatitis: A Multicentre, Randomised, Double-Blind, Placebo-Controlled, Phase 2 Trial. Lancet 2018, 391, 1174– 1185,  DOI: 10.1016/S0140-6736(18)30474-4

     [Crossref], [PubMed], [CAS], Google Scholar

     103

     NGM282 for treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial

     Harrison, Stephen A.; Rinella, Mary E.; Abdelmalek, Manal F.; Trotter, James F.; Paredes, Angelo H.; Arnold, Hays L.; Kugelmas, Marcelo; Bashir, Mustafa R.; Jaros, Mark J.; Ling, Lei; Rossi, Stephen J.; De Paoli, Alex M.; Loomba, Rohit

     Lancet (2018), 391 (10126), 1174-1185CODEN: LANCAO; ISSN:0140-6736. (Elsevier Ltd.)

     Non-alc. steatohepatitis is a chronic liver disease characterised by the presence of hepatic steatosis, inflammation, and hepatocellular injury, for which no Food and Drug Administration (FDA)-approved treatment exists. FGF19 is a hormone that regulates bile acid synthesis and glucose homoeostasis. We aimed to assess the safety and efficacy of NGM282, an engineered FGF19 analog, for the treatment of non-alc. steatohepatitis. In this randomised, double-blind, placebo-controlled, phase 2 study, we recruited patients aged 18-75 years with biopsy-confirmed non-alc. steatohepatitis as defined by the non-alc. steatohepatitis clin. research network histol. scoring system, from hospitals and gastroenterol. and liver clinics in Australia and the USA. Key eligibility criteria included a non-alc. fatty liver disease activity score of 4 or higher, stage 1-3 fibrosis, and at least 8% liver fat content. Patients were randomly assigned (1:1:1) via a web-based system and stratified by diabetic status to receive either 3 mg or 6 mg s.c. NGM282 or placebo. The primary endpoint was the abs. change from baseline to week 12 in liver fat content. Responders were patients who achieved a 5% or larger redn. in abs. liver fat content as measured by MRI-proton d. fat fraction. Efficacy anal. was by intention to treat. This trial is registered with ClinicalTrials.gov, no. NCT02443116. Between July 14, 2015, and Aug 30, 2016, 166 patients were screened across 18 sites in Australia and the USA. 82 patients were randomly assigned to receive 3 mg NGM282 (n=27), 6 mg NGM282 (n=28), or placebo (n=27). At 12 wk, 20 (74%) patients in the 3 mg dose group and 22 (79%) in the 6 mg dose group achieved at least a 5% redn. in abs. liver fat content from baseline (relative risk 10·0 [95% CI 2·6-38·7] vs 11·4 [3·0-43·8], resp.; p<0·0001 for both comparisons) vs. two (7%) in the placebo group. Overall, 76 (93%) of 82 patients experienced at least one adverse event, most of which were grade 1 (55 [67%]), and only five (6%) were grade 3 or worse. The most commonly (≥10%) reported adverse events were injection site reactions (28 [34%]), diarrhoea (27 [33%]), abdominal pain (15 [18%]), and nausea (14 [17%]). These adverse events were reported more frequently in the NGM282 groups compared with the placebo group. No life-threatening events or patient deaths occurred during the study. NGM282 produced rapid and significant redns. in liver fat content with an acceptable safety profile in patients with non-alc. steatohepatitis. Further study of NGM282 is warranted in this patient population.NGM Biopharmaceuticals.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXjvFyntro%253D&md5=6f668d7f1fa04bd0a22aa65bca1f1132

     
104. 104

     Sanyal, A.; Charles, E. D.; Neuschwander-Tetri, B. A.; Loomba, R.; Harrison, S. A.; Abdelmalek, M. F.; Lawitz, E. J.; Halegoua-DeMarzio, D.; Kundu, S.; Noviello, S.; Luo, Y.; Christian, R. Pegbelfermin (BMS-986036), a PEGylated Fibroblast Growth Factor 21 Analogue, in Patients with Non-Alcoholic Steatohepatitis: A Randomised, Double-Blind, Placebo-Controlled, Phase 2a Trial. Lancet 2018, 392, 2705– 2717,  DOI: 10.1016/S0140-6736(18)31785-9

     [Crossref], [PubMed], [CAS], Google Scholar

     104

     Pegbelfermin (BMS-986036), a PEGylated fibroblast growth factor 21 analogue, in patients with non-alcoholic steatohepatitis: a randomised, double-blind, placebo-controlled, phase 2a trial

     Sanyal, Arun; Charles, Edgar D.; Neuschwander-Tetri, Brent A.; Loomba, Rohit; Harrison, Stephen A.; Abdelmalek, Manal F.; Lawitz, Eric J.; Halegoua-DeMarzio, Dina; Kundu, Sudeep; Noviello, Stephanie; Luo, Yi; Christian, Rose

     Lancet (2018), 392 (10165), 2705-2717CODEN: LANCAO; ISSN:0140-6736. (Elsevier Ltd.)

     Pegbelfermin (BMS-986036), a PEGylated human fibroblast growth factor 21 (FGF21) analog, has previously been shown to improve markers of metab. and liver fibrosis in obese patients with type 2 diabetes. In this phase 2a study, we aimed to evaluate the safety and efficacy of pegbelfermin in patients with non-alc. steatohepatitis. In this multicentre, randomised, double-blind, placebo-controlled, parallel-group, phase 2a study, we recruited adults (aged 21-75 years) with a body-mass index of at least 25 kg/m2, biopsy-confirmed non-alc. steatohepatitis (fibrosis stage 1-3), and a hepatic fat fraction of at least 10% when assessed by magnetic resonance imaging-proton d. fat fraction. These patients were enrolled at 17 medical centers in the USA. Eligible patients were stratified by type 2 diabetes status and they were randomly assigned (1:1:1) by a computer-based system to receive s.c. injections of placebo once a day, 10 mg pegbelfermin once a day, or 20 mg pegbelfermin once a week, all for 16 wk. Participants, the study team administering treatment, and investigators analyzing outcomes (who were independent of the study team and had no further involvement) were masked to treatment groups. The primary outcomes were safety and the abs. change in hepatic fat fraction after 16 wk of treatment. All patients who were randomly assigned to groups and received the study drug or placebo were included in the primary analyses. This trial was registered with ClinicalTrials.gov, no. NCT02413372. Between May 12, 2015, and Aug 4, 2016, 184 overweight or obese patients with non-alc. steatohepatitis were screened for study inclusion. Of these, 95 (52%) patients were excluded because they no longer met study criteria and 80 (43%) patients entered the placebo lead-in phase. After further exclusions, 75 (94%) patients were randomly assigned to groups, received at least one dose of treatment (25 patients to receive 10 mg pegbelfermin once a day; 24 patients to receive 20 mg pegbelfermin once a week, and 26 patients to receive placebo), and were included in the primary anal. A prespecified interim anal. at week 8 showed a greater than expected change in the primary outcome and supported early closing of patient enrolment, since this anal. indicated that the full planned sample size was not needed. We obsd. a significant decrease in abs. hepatic fat fraction in the group receiving 10 mg pegbelfermin daily (-6·8% vs -1·3%; p=0·0004) and in the group receiving 20 mg pegbelfermin weekly (-5·2% vs -1·3%; p=0·008) compared with the placebo group. Most adverse events were mild; the most common events were diarrhoea in eight (16%) of 49 patients treated with pegbelfermin and two (8%) of 26 patients treated with placebo and nausea in seven (14%) patients treated with pegbelfermin and two (8%) patients treated with placebo. There were no deaths, discontinuations due to adverse events, or treatment-related serious adverse events. Treatment with s.c. administered pegbelfermin for 16 wk was generally well tolerated and significantly reduced hepatic fat fraction in patients with non-alc. steatohepatitis. Further study of pegbelfermin is warranted in patients with non-alc. steatohepatitis. Addnl. studies that use liver biopsies would allow for the assessment of pegbelfermin's effects on liver histol. Moreover, further studies should allow assessments of the safety and effectiveness of pegbelfermin in a larger no. of patients.Bristol-Myers Squibb.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXisFekurzJ&md5=55fd041f4c8ec3a8d13c7df6d897375a

     
105. 105

     Kopec, K. K.; Liu, P. M. Mutant FGF-21 Peptide Conjugates and Uses Thereof. International Patent WO2019043457, 2019.

     Google Scholar

     There is no corresponding record for this reference.

     
106. 106

     Beg, Z. H.; Allmann, D. W.; Gibson, D. M. Modulation of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Activity with cAMP and with Protein Fractions of Rat Liver Cytosol. Biochem. Biophys. Res. Commun. 1973, 54, 1362– 1369,  DOI: 10.1016/0006-291X(73)91137-6

     [Crossref], [PubMed], [CAS], Google Scholar

     106

     Modulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity with cyclic AMP and with protein fractions of rat liver cytosol

     Beg, Zafarul H.; Allmann, David W.; Gibson, David M.

     Biochemical and Biophysical Research Communications (1973), 54 (4), 1362-9CODEN: BBRCA9; ISSN:0006-291X.

     3-Hydroxy-3-methylglutaryl-CoA reductase activity is diminished in several in vitro liver systems preincubated in the presence of cyclic AMP. Reductase activity in isolated, washed liver microsomes is inactivated by ATP, Mg2+, and a protein fraction sepd. from the liver cytosol. This effect is augmented by cyclic AMP. Reductase activity in previously inactivated microsomes can be partially restored by incubation with a 2nd protein fraction of the cytosol.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE3sXlsVers7s%253D&md5=6439be4bdbd3978d96c914351bd95d30

     
107. 107

     Carlson, C. A.; Kim, K. H. Regulation of Hepatic Acetyl Coenzyme A Carboxylase by Phosphorylation and Dephosphorylation. Arch. Biochem. Biophys. 1974, 164, 478– 489,  DOI: 10.1016/0003-9861(74)90058-7

     [Crossref], [PubMed], [CAS], Google Scholar

     107

     Regulation of hepatic acetyl coenzyme A carboxylase by phosphorylation and dephosphorylation

     Carlson, Curtis A.; Kim, Ki-Han

     Archives of Biochemistry and Biophysics (1974), 164 (2), 478-89CODEN: ABBIA4; ISSN:0003-9861.

     A partially purified prepn. of acetyl CoA carboxylase was inactivated by ATP in a time- and temp.-dependent reaction. Cyclic AMP did not affect the inactivation. Further purifn. sepd. the carboxylase from a protein fraction which greatly enhanced the inactivation of the enzyme. Inactivation of the enzyme with 32P-labeled ATP resulted in the incorporation of 32P which copurified with the enzyme. When carboxylase inactivated by exposure to ATP was pptd. with antibody, isotope incorporation into the ppt. paralleled enzyme inactivation. The phosphate was bound to serine and threonine residues by an ester linkage. NaF completely inhibited the activation of partially purified enzyme by Mg2+. Activation by Mg2+ accompanied by the release of protein-bound 32P, was antagonistic to inactivation of the enzyme by ATP. The data are consistent with a mechanism for controlling acetyl CoA carboxylase activity by interconversion between phosphorylated and dephosphorylated forms. Phosphorylation of the enzyme by a protein kinase decreases enzyme activity, whereas dephosphorylation by a protein phosphatase reactivates the enzyme.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE2MXht12htg%253D%253D&md5=dacb1cfce8912a004123cc55b3b54c58

     
108. 108

     Rana, S.; Blowers, E. C.; Natarajan, A. Small Molecule Adenosine 5′-Monophosphate Activated Protein Kinase (AMPK) Modulators and Human Diseases. J. Med. Chem. 2015, 58, 2– 29,  DOI: 10.1021/jm401994c

     [ACS Full Text ], [CAS], Google Scholar

     108

     Small Molecule Adenosine 5'-Monophosphate Activated Protein Kinase (AMPK) Modulators and Human Diseases

     Rana, Sandeep; Blowers, Elizabeth C.; Natarajan, Amarnath

     Journal of Medicinal Chemistry (2015), 58 (1), 2-29CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

     A review. AMP activated protein kinase (AMPK) is a master sensor of cellular energy status that plays a key role in the regulation of whole-body energy homeostasis. AMPK is a serine/threonine kinase that is activated by upstream kinases LKB1, CaMKKβ, and Tak1, among others. AMPK exists as αβγ trimeric complexes that are allosterically regulated by AMP, ADP, and ATP. Dysregulation of AMPK has been implicated in a no. of metabolic diseases including type 2 diabetes mellitus and obesity. Recent studies have assocd. roles of AMPK with the development of cancer and neurol. disorders, making it a potential therapeutic target to treat human diseases. This review focuses on the structure and function of AMPK, its role in human diseases, and its direct substrates and provides a brief synopsis of key AMPK modulators and their relevance in human diseases.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtlKlu7jM&md5=22a696a164817998346c56dc5de26949

     
109. 109

     Steinberg, G. R.; Carling, D. AMP-Activated Protein Kinase: The Current Landscape for Drug Development. Nat. Rev. Drug Discovery 2019, 18, 527– 551,  DOI: 10.1038/s41573-019-0019-2

     [Crossref], [PubMed], [CAS], Google Scholar

     109

     AMP-activated protein kinase: the current landscape for drug development

     Steinberg, Gregory R.; Carling, David

     Nature Reviews Drug Discovery (2019), 18 (7), 527-551CODEN: NRDDAG; ISSN:1474-1776. (Nature Research)

     Since the discovery of AMP-activated protein kinase (AMPK) as a central regulator of energy homeostasis, many exciting insights into its structure, regulation and physiol. roles have been revealed. While exercise, caloric restriction, metformin and many natural products increase AMPK activity and exert a multitude of health benefits, developing direct activators of AMPK to elicit beneficial effects has been challenging. However, in recent years, direct AMPK activators have been identified and tested in preclin. models, and a small no. have entered clin. trials. Despite these advances, which disease(s) represent the best indications for therapeutic AMPK activation and the long-term safety of such approaches remain to be established.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXms1Gks74%253D&md5=3185a2c8a78cc3bc202703387dc0af1b

     
110. 110

     Carling, D.; Hardie, D. G. The Substrate and Sequence Specificity of the AMP-Activated Protein Kinase. Phosphorylation of Glycogen Synthase and Phosphorylase Kinase. Biochim. Biophys. Acta, Mol. Cell Res. 1989, 1012, 81– 86,  DOI: 10.1016/0167-4889(89)90014-1

     [Crossref], [PubMed], [CAS], Google Scholar

     110

     The substrate and sequence specificity of the AMP-activated protein kinase. Phosphorylation of glycogen synthase and phosphorylase kinase

     Carling, David; Hardie, D. Grahame

     Biochimica et Biophysica Acta, Molecular Cell Research (1989), 1012 (1), 81-6CODEN: BBAMCO; ISSN:0167-4889.

     In addn. to acetyl-CoA carboxylase and hydroxymethylglutaryl-CoA reductase, rat liver AMP-activated protein kinase phosphorylated glycogen synthase, phosphorylase kinase, hormone-sensitive lipase, and casein. A no. of other substrates for cAMP-dependent protein kinase, e.g., pyruvate kinase and 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase, were not phosphorylated at significant rates. Examn. of the sites phosphorylated on acetyl-CoA carboxylase, hormone-sensitive lipase, glycogen synthase, and phosphorylase kinase suggested a consensus recognition sequence in which the serine residue phosphorylated by the AMP-activated protein kinase has a hydrophobic residue on the N-terminal side (i.e., at position -1) and ≥1 arginine residue at positions -2, -3 or -4. Substrates for cAMP-dependent protein kinase which lack the hydrophobic residue at position -1 were not substrates for the AMP-activated protein kinase.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL1MXktlGltrY%253D&md5=a87db79aaf0c237b3d3fc2f6426536b3

     
111. 111

     Suter, M.; Riek, U.; Tuerk, R.; Schlattner, U.; Wallimann, T.; Neumann, D. Dissecting the Role of 5′-AMP for Allosteric Stimulation, Activation, and Deactivation of AMP-Activated Protein Kinase. J. Biol. Chem. 2006, 281, 32207– 32216,  DOI: 10.1074/jbc.M606357200

     [Crossref], [PubMed], [CAS], Google Scholar

     111

     Dissecting the Role of 5'-AMP for Allosteric Stimulation, Activation, and Deactivation of AMP-activated Protein Kinase

     Suter, Marianne; Riek, Uwe; Tuerk, Roland; Schlattner, Uwe; Wallimann, Theo; Neumann, Dietbert

     Journal of Biological Chemistry (2006), 281 (43), 32207-32216CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)

     AMP-activated protein kinase (AMPK) is a heterotrimeric protein kinase that is crucial for cellular energy homeostasis of eukaryotic cells and organisms. Here we report on the activation of AMPK α1β1γ1 and α2β2γ1 by their upstream kinases (Ca2+/calmodulin-dependent protein kinase kinase-β and LKB1-MO25α-STRADα), deactivation by protein phosphatase 2Cα (PP2Cα), and the extent of stimulation of AMPK by its allosteric activator AMP, using purified recombinant enzyme prepns. An accurate high pressure liq. chromatog. (HPLC)-based method for AMPK activity measurements was established, which allowed for direct quantitation of the unphosphorylated and phosphorylated artificial peptide substrate, as well as the adenine nucleotides. Our results show a 1000-fold activation of AMPK by the combined effects of upstream kinase and satg. concns. of AMP. The two AMPK isoforms exhibit similar specific activities (6 μmol/min/mg) and do not differ significantly by their responsiveness to AMP. Due to the inherent instability of ATP and ADP, it proved impossible to assay AMPK activity in the abs. absence of AMP. However, the half-maximal stimulatory effect of AMP is reached below 2 μM. AMP does not appear to augment phosphorylation by upstream kinases in the purified in vitro system, but deactivation by dephosphorylation of AMPK α-subunits at Thr-172 by protein phosphatase 2Cα is attenuated by AMP. Furthermore, it is shown that neither purified NAD+ nor NADH alters the activity of AMPK in a concn. range of 0-300 μM, resp. Finally, evidence is provided that ZMP, a compd. formed in 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR)-treated cells to activate AMPK in vivo, allosterically activates purified AMPK in vitro, but compared with AMP, maximal activity is not reached. These data shed new light on physiol. important aspects of AMPK regulation.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XhtFSrsbnE&md5=d878ffbbd7aa481f314ba8c9b508e0ab

     
112. 112

     Hardie, D. G. The AMP-Activated Protein Kinase Pathway–New Players Upstream and Downstream. J. Cell Sci. 2004, 117, 5479– 5487,  DOI: 10.1242/jcs.01540

     [Crossref], [PubMed], [CAS], Google Scholar

     112

     The AMP-activated protein kinase pathway - new players upstream and downstream

     Hardie, D. Grahame

     Journal of Cell Science (2004), 117 (23), 5479-5487CODEN: JNCSAI; ISSN:0021-9533. (Company of Biologists Ltd.)

     A review. The AMP-activated protein kinase (AMPK) cascade is a sensor of cellular energy status. Whenever the cellular ATP:ADP ratio falls, owing to a stress that inhibits ATP prodn. or increases ATP consumption, this is amplified by adenylate kinase into a much larger increase in the AMP:ATP ratio. AMP activates the system by binding to two tandem domains on the γ subunits of AMPK, and this is antagonized by high concns. of ATP. AMP binding causes activation by a sensitive mechanism involving phosphorylation of AMPK by the tumor suppressor LKB1. Once activated, AMPK switches on catabolic pathways that generate ATP while switching off ATP-consuming processes. As well as acting at the level of the individual cell, the system also regulates food intake and energy expenditure at the whole body level, in particular by mediating the effects of hormones and cytokines such as leptin, adiponectin and ghrelin. A particularly interesting downstream target recently identified is TSC2 (tuberin). The LKB1→AMPK→TSC2 pathway neg. regulates the target of rapamycin (TOR), and this appears to be responsible for limiting protein synthesis and cell growth, and protecting against apoptosis, during cellular stresses such as glucose starvation.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXhtFagur7N&md5=ddbe7b38a1b810707923d724344ed243

     
113. 113

     Ha, J.; Daniel, S.; Broyles, S. S.; Kim, K. H. Critical Phosphorylation Sites for Acetyl-CoA Carboxylase Activity. J. Biol. Chem. 1994, 269, 22162– 22168

     [PubMed], [CAS], Google Scholar

     113

     Critical phosphorylation sites for acetyl-CoA carboxylase activity

     Ha, Joohun; Daniel, Samira; Broyles, Steven S.; Kim, Ki-Han

     Journal of Biological Chemistry (1994), 269 (35), 22162-8CODEN: JBCHA3; ISSN:0021-9258.

     Acetyl-CoA carboxylase (ACC) is rapidly regulated by reversible phosphorylation; phosphorylation inactivates ACC, whereas dephosphorylation activates the enzyme. Among protein kinases only cAMP-dependent protein kinase (protein kinase A) (I) and AMP-dependent protein kinase (II) can inactivate ACC; I phosphorylates Ser-77 and Ser-1200, whereas II phosphorylates Ser-79, Ser-1200, and Ser-1215. Here, the construction and expression of ACC cDNA contg. the entire coding region (7.2 kb pairs) is described. In order to identify the crit. phosphorylation site(s) for each protein kinase, site-specific mutations were introduced at Ser-77, Ser-79, Ser-1200, and Ser-1215 of ACC cDNA and a series of mutated ACCs contg. various combinations of these 4 mutated sites was expressed. By examn. of the various mutant ACCs, evidence was obtained that the effect of I is entirely mediated by the phosphorylation of Ser-1200 and that Ser-79 is important II inn vitro.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2cXlsleruro%253D&md5=ca0ca0737b87d0e815b2fe6e26cd9f58

     
114. 114

     Ross, F. A.; MacKintosh, C.; Hardie, D. G. AMP-Activated Protein Kinase: A Cellular Energy Sensor that Comes in 12 Flavours. FEBS J. 2016, 283, 2987– 3001,  DOI: 10.1111/febs.13698

     [Crossref], [PubMed], [CAS], Google Scholar

     114

     AMP-activated protein kinase: a cellular energy sensor that comes in 12 flavours

     Ross, Fiona A.; MacKintosh, Carol; Hardie, D. Grahame

     FEBS Journal (2016), 283 (16), 2987-3001CODEN: FJEOAC; ISSN:1742-464X. (Wiley-Blackwell)

     A review. The AMP-activated protein kinase (AMPK) is a sensor of cellular energy status that is expressed in essentially all eukaryotic cells, suggesting that it arose during early eukaryotic evolution. It occurs universally as heterotrimeric complexes contg. catalytic α subunits and regulatory β and γ subunits. Although Drosophila melanogaster contains single genes encoding each subunit, in mammals, each subunit exists as multiple isoforms encoded by distinct genes, giving rise to up to 12 heterotrimeric combinations. The multiple isoforms of each subunit are 2R-ohnologues generated by the two rounds of whole genome duplication that occurred at the evolutionary origin of the vertebrates. Although the differential roles of these isoform combinations remain only partly understood, there are indications that they may have different subcellular locations, different inputs and outputs, and different functions. The multiple isoforms are of particular interest with respect to the roles of AMPK in cancer because the genes encoding some isoforms, such as PRKAA1 and PRKAB2 (encoding α1 and β2), are quite frequently amplified in tumor cells, whereas the genes encoding others, such as PRKAA2 (encoding α2), tend to be mutated, which, in some but not all cases, may result in a loss of function. Thus, although AMPK acts downstream of the tumor suppressor liver kinase B1, and some of its isoform combinations may act as tumor suppressors that restrain the growth and proliferation of tumor cells, other isoform combinations may paradoxically act as oncogenes, perhaps by aiding the survival of tumor cells undergoing environmental stresses such as hypoxia or nutrient deprivation.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XkvVSjtro%253D&md5=0b65385fe0f4973621e06b0a204c15aa

     
115. 115

     Steinberg, G. R.; Kemp, B. E. AMPK in Health and Disease. Physiol. Rev. 2009, 89, 1025– 1078,  DOI: 10.1152/physrev.00011.2008

     [Crossref], [PubMed], [CAS], Google Scholar

     115

     AMPK in health and disease

     Steinberg, Gregory R.; Kemp, Bruce E.

     Physiological Reviews (2009), 89 (3), 1025-1078CODEN: PHREA7; ISSN:0031-9333. (American Physiological Society)

     A review. The function and survival of all organisms is dependent on the dynamic control of energy metab., when energy demand is matched to energy supply. The AMP-activated protein kinase (AMPK) αβγ heterotrimer has emerged as an important integrator of signals that control energy balance through the regulation of multiple biochem. pathways in all eukaryotes. In this review, we begin with the discovery of the AMPK family and discuss the recent structural studies that have revealed the mol. basis for AMP binding to the enzyme's γ subunit. AMPK's regulation involves autoinhibitory features and phosphorylation of both the catalytic α subunit and the β-targeting subunit. We review the role of AMPK at the cellular level through examn. of its many substrates and discuss how it controls cellular energy balance. We look at how AMPK integrates stress responses such as exercise as well as nutrient and hormonal signals to control food intake, energy expenditure, and substrate utilization at the whole body level. Lastly, we review the possible role of AMPK in multiple common diseases and the role of the new age of drugs targeting AMPK signaling.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXpslyjsb4%253D&md5=fbc46b4e8edc695c24da582889bfc9a2

     
116. 116

     Wu, J.; Puppala, D.; Feng, X.; Monetti, M.; Lapworth, A. L.; Geoghegan, K. F. Chemoproteomic Analysis of Intertissue and Interspecies Isoform Diversity of AMP-Activated Protein Kinase (AMPK). J. Biol. Chem. 2013, 288, 35904– 35912,  DOI: 10.1074/jbc.M113.508747

     [Crossref], [PubMed], [CAS], Google Scholar

     116

     Chemoproteomic Analysis of Intertissue and Interspecies Isoform Diversity of AMP-activated Protein Kinase (AMPK)

     Wu, Jiang; Puppala, Dinesh; Feng, Xidong; Monetti, Mara; Lapworth, Amanda Lee; Geoghegan, Kieran F.

     Journal of Biological Chemistry (2013), 288 (50), 35904-35912CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)

     AMP-activated protein kinase (AMPK) is a heterotrimeric enzyme that senses and governs changes in the cellular energy balance represented by concns. of AMP, ADP, and ATP. Each of its three chains (α, β, and γ) exists as either two or three subtypes, theor. allowing up to 12 different forms of the complete enzyme. Tissue specificity in the distribution of AMPK subtypes is believed to underpin a range of biol. functions for AMPK, a central regulator of metabolic function and response. It is of particular interest for drug discovery purposes to compare AMPK isoforms that are most prevalent in human liver and muscle with isoforms present in key preclin. species. To complement immunocapture/immunodetection methods, which for AMPK are challenged by sequence similarities and difficulties of obtaining accurate relative quantitation, AMPK was captured from lysates of a range of cells and tissues using the ActivX ATP probe. This chem. probe covalently attaches desthiobiotin to one or more conserved lysyl residues in the ATP-binding sites of protein kinases, including AMPK, while also labeling a wide range of ATP-utilizing proteins. Affinity-based recovery of labeled proteins followed by gel-based fractionation of the captured sample was followed by proteomic characterization of AMPK polypeptides. In agreement with transcript-based anal. and previous indications from immunodetection, the results indicated that the predominant AMPK heterotrimer in human liver is α1β2γ1 but that dog and rat livers mainly contain the α1β1γ1 and α2β1γ1 forms, resp. Differences were not detected between the AMPK profiles of normal and diabetic human liver tissues.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvFars7jM&md5=3a4b7aa1268fe2bd6d460d319bf48b0b

     
117. 117

     Cool, B.; Zinker, B.; Chiou, W.; Kifle, L.; Cao, N.; Perham, M.; Dickinson, R.; Adler, A.; Gagne, G.; Iyengar, R.; Zhao, G.; Marsh, K.; Kym, P.; Jung, P.; Camp, H. S.; Frevert, E. Identification and Characterization of a Small Molecule AMPK Activator that Treats Key Components of Type 2 Diabetes and the Metabolic Syndrome. Cell Metab. 2006, 3, 403– 416,  DOI: 10.1016/j.cmet.2006.05.005

     [Crossref], [PubMed], [CAS], Google Scholar

     117

     Identification and characterization of a small molecule AMPK activator that treats key components of type 2 diabetes and the metabolic syndrome

     Cool, Barbara; Zinker, Bradley; Chiou, William; Kifle, Lemma; Cao, Ning; Perham, Matthew; Dickinson, Robert; Adler, Andrew; Gagne, Gerard; Iyengar, Rajesh; Zhao, Gang; Marsh, Kennan; Kym, Philip; Jung, Paul; Camp, Heidi S.; Frevert, Ernst

     Cell Metabolism (2006), 3 (6), 403-416CODEN: CMEEB5; ISSN:1550-4131. (Cell Press)

     AMP-activated protein kinase (AMPK) is a key sensor and regulator of intracellular and whole-body energy metab. The authors have identified a thienopyridone family of AMPK activators. A-769662 directly stimulated partially purified rat liver AMPK (EC50 = 0.8 μM) and inhibited fatty acid synthesis in primary rat hepatocytes (IC50 = 3.2 μM). Short-term treatment of normal Sprague Dawley rats with A-769662 decreased liver malonyl Co-A levels and the respiratory exchange ratio, VCO2/VO2, indicating an increased rate of whole-body fatty acid oxidn. Treatment of ob/ob mice with 30 mg/kg b.i.d. A-769662 decreased hepatic expression of PEPCK, G6Pase, and FAS, lowered plasma glucose by 40%, reduced body wt. gain and significantly decreased both plasma and liver triglyceride levels. These results demonstrate that small mol. mediated activation of AMPK in vivo is feasible and represents a promising approach for the treatment of type 2 diabetes and the metabolic syndrome.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xmt1eku70%253D&md5=710c43b18664c5f29b9cdd5dee5e9e90

     
118. 118

     Cameron, K. O.; Kung, D. W.; Kalgutkar, A. S.; Kurumbail, R. G.; Miller, R.; Salatto, C. T.; Ward, J.; Withka, J. M.; Bhattacharya, S. K.; Boehm, M.; Borzilleri, K. A.; Brown, J. A.; Calabrese, M.; Caspers, N. L.; Cokorinos, E.; Conn, E. L.; Dowling, M. S.; Edmonds, D. J.; Eng, H.; Fernando, D. P.; Frisbie, R.; Hepworth, D.; Landro, J.; Mao, Y.; Rajamohan, F.; Reyes, A. R.; Rose, C. R.; Ryder, T.; Shavnya, A.; Smith, A. C.; Tu, M.; Wolford, A. C.; Xiao, J. Discovery and Preclinical Characterization of 6-Chloro-5-[4-(1-hydroxycyclobutyl)phenyl]-1H-indole-3-carboxylic Acid (PF-06409577), a Direct Activator of Adenosine Monophosphate-Activated Protein Kinase (AMPK), for the Potential Treatment of Diabetic Nephropathy. J. Med. Chem. 2016, 59, 8068– 8081,  DOI: 10.1021/acs.jmedchem.6b00866

     [ACS Full Text ], [CAS], Google Scholar

     118

     Discovery and Preclinical Characterization of 6-Chloro-5-[4-(1-hydroxycyclobutyl)phenyl]-1H-indole-3-carboxylic Acid (PF-06409577), a Direct Activator of Adenosine Monophosphate-activated Protein Kinase (AMPK), for the Potential Treatment of Diabetic Nephropathy

     Cameron, Kimberly O.; Kung, Daniel W.; Kalgutkar, Amit S.; Kurumbail, Ravi G.; Miller, Russell; Salatto, Christopher T.; Ward, Jessica; Withka, Jane M.; Bhattacharya, Samit K.; Boehm, Markus; Borzilleri, Kris A.; Brown, Janice A.; Calabrese, Matthew; Caspers, Nicole L.; Cokorinos, Emily; Conn, Edward L.; Dowling, Matthew S.; Edmonds, David J.; Eng, Heather; Fernando, Dilinie P.; Frisbie, Richard; Hepworth, David; Landro, James; Mao, Yuxia; Rajamohan, Francis; Reyes, Allan R.; Rose, Colin R.; Ryder, Tim; Shavnya, Andre; Smith, Aaron C.; Tu, Meihua; Wolford, Angela C.; Xiao, Jun

     Journal of Medicinal Chemistry (2016), 59 (17), 8068-8081CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

     Adenosine monophosphate-activated protein kinase (AMPK) is a protein kinase involved in maintaining energy homeostasis within cells. On the basis of human genetic assocn. data, AMPK activators were pursued for the treatment of diabetic nephropathy. Identification of an indazole amide high throughput screening (HTS) hit followed by truncation to its minimal pharmacophore provided an indazole acid lead compd. Optimization of the core and aryl appendage improved oral absorption and culminated in the identification of indole acid, PF-06409577 (7). Compd. 7 was advanced to first-in-human trials for the treatment of diabetic nephropathy.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xht12gtb%252FI&md5=0b70014081c86df1cf3d713ab943d39c

     
119. 119

     Esquejo, R. M.; Salatto, C. T.; Delmore, J.; Albuquerque, B.; Reyes, A.; Shi, Y.; Moccia, R.; Cokorinos, E.; Peloquin, M.; Monetti, M.; Barricklow, J.; Bollinger, E.; Smith, B. K.; Day, E. A.; Nguyen, C.; Geoghegan, K. F.; Kreeger, J. M.; Opsahl, A.; Ward, J.; Kalgutkar, A. S.; Tess, D.; Butler, L.; Shirai, N.; Osborne, T. F.; Steinberg, G. R.; Birnbaum, M. J.; Cameron, K. O.; Miller, R. A. Activation of Liver AMPK with PF-06409577 Corrects NAFLD and Lowers Cholesterol in Rodent and Primate Preclinical Models. EBioMedicine 2018, 31, 122– 132,  DOI: 10.1016/j.ebiom.2018.04.009

     [Crossref], [PubMed], [CAS], Google Scholar

     119

     Activation of Liver AMPK with PF-06409577 Corrects NAFLD and Lowers Cholesterol in Rodent and Primate Preclinical Models

     Esquejo Ryan M; Salatto Christopher T; Delmore Jake; Albuquerque Bina; Reyes Allan; Shi Yuji; Cokorinos Emily; Peloquin Matthew; Monetti Mara; Bollinger Eliza; Ward Jessica; Birnbaum Morris J; Moccia Rob; Barricklow Jason; Smith Brennan K; Day Emily A; Steinberg Gregory R; Nguyen Chuong; Geoghegan Kieran F; Kreeger John M; Opsahl Alan; Butler Lynne; Shirai Norimitsu; Kalgutkar Amit S; Tess David; Osborne Timothy F; Cameron Kimberly O; Miller Russell A

     EBioMedicine (2018), 31 (), 122-132 ISSN:.

     Dysregulation of hepatic lipid and cholesterol metabolism is a significant contributor to cardiometabolic health, resulting in excessive liver lipid accumulation and ultimately non-alcoholic steatohepatitis (NASH). Therapeutic activators of the AMP-Activated Protein Kinase (AMPK) have been proposed as a treatment for metabolic diseases; we show that the AMPK β1-biased activator PF-06409577 is capable of lowering hepatic and systemic lipid and cholesterol levels in both rodent and monkey preclinical models. PF-06409577 is able to inhibit de novo lipid and cholesterol synthesis pathways, and causes a reduction in hepatic lipids and mRNA expression of markers of hepatic fibrosis. These effects require AMPK activity in the hepatocytes. Treatment of hyperlipidemic rats or cynomolgus monkeys with PF-06409577 for 6weeks resulted in a reduction in circulating cholesterol. Together these data suggest that activation of AMPK β1 complexes with PF-06409577 is capable of impacting multiple facets of liver disease and represents a promising strategy for the treatment of NAFLD and NASH in humans.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1MjksFCquw%253D%253D&md5=b566de696f76e623975433c49ea94ddf

     
120. 120

     Lan, P.; Romero, F. A.; Wodka, D.; Kassick, A. J.; Dang, Q.; Gibson, T.; Cashion, D.; Zhou, G.; Chen, Y.; Zhang, X.; Zhang, A.; Li, Y.; Trujillo, M. E.; Shao, Q.; Wu, M.; Xu, S.; He, H.; MacKenna, D.; Staunton, J.; Chapman, K. T.; Weber, A.; Sebhat, I. K.; Makara, G. M. Hit-to-Lead Optimization and Discovery of 5-((5-([1,1’-Biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic Acid (MK-3903): A Novel Class of Benzimidazole-Based Activators of AMP-Activated Protein Kinase. J. Med. Chem. 2017, 60, 9040– 9052,  DOI: 10.1021/acs.jmedchem.7b01344

     [ACS Full Text ], [CAS], Google Scholar

     120

     Hit-to-Lead Optimization and Discovery of 5-((5-([1,1'-Biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic Acid (MK-3903): A Novel Class of Benzimidazole-Based Activators of AMP-Activated Protein Kinase

     Lan, Ping; Romero, F. Anthony; Wodka, Dariusz; Kassick, Andrew J.; Dang, Qun; Gibson, Tony; Cashion, Daniel; Zhou, Gaochao; Chen, Yuli; Zhang, Xiaoping; Zhang, Aihua; Li, Ying; Trujillo, Maria E.; Shao, Qing; Wu, Margaret; Xu, Shiyao; He, Huaibing; MacKenna, Deidre; Staunton, Jocelyn; Chapman, Kevin T.; Weber, Ann; Sebhat, Iyassu K.; Makara, Gergely M.

     Journal of Medicinal Chemistry (2017), 60 (21), 9040-9052CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

     AMP-activated protein kinase (AMPK) plays an essential role as a cellular energy sensor and master regulator of metab. in eukaryotes. Dysregulated lipid and carbohydrate metab. resulting from insulin resistance leads to hyperglycemia, the hallmark of type 2 diabetes mellitus (T2DM). While pharmacol. activation of AMPK is anticipated to improve these parameters, the discovery of selective, direct activators has proven challenging. The authors now describe a hit-to-lead effort resulting in the discovery of a potent and selective class of benzimidazole-based direct AMPK activators, exemplified by 5-((5-([1,1'-biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid, (I) (MK-3903). Compd. I exhibited robust target engagement in mouse liver following oral dosing, leading to improved lipid metab. and insulin sensitization in mice.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhs1Kns77K&md5=83e7343b1bfa589036c3bcb5ab8e62c1

     
121. 121

     Feng, D.; Biftu, T.; Romero, F. A.; Kekec, A.; Dropinski, J.; Kassick, A.; Xu, S.; Kurtz, M. M.; Gollapudi, A.; Shao, Q.; Yang, X.; Lu, K.; Zhou, G.; Kemp, D.; Myers, R. W.; Guan, H. P.; Trujillo, M. E.; Li, C.; Weber, A.; Sebhat, I. K. Discovery of MK-8722: A Systemic, Direct Pan-Activator of AMP-Activated Protein Kinase. ACS Med. Chem. Lett. 2018, 9, 39– 44,  DOI: 10.1021/acsmedchemlett.7b00417

     [ACS Full Text ], [CAS], Google Scholar

     121

     Discovery of MK-8722: A Systemic, Direct Pan-Activator of AMP-Activated Protein Kinase

     Feng, Danqing; Biftu, Tesfaye; Romero, F. Anthony; Kekec, Ahmet; Dropinski, James; Kassick, Andrew; Xu, Shiyao; Kurtz, Marc M.; Gollapudi, Anantha; Shao, Qing; Yang, Xiaodong; Lu, Ku; Zhou, Gaochao; Kemp, Daniel; Myers, Robert W.; Guan, Hong-Ping; Trujillo, Maria E.; Li, Cai; Weber, Ann; Sebhat, Iyassu K.

     ACS Medicinal Chemistry Letters (2018), 9 (1), 39-44CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)

     5'-Adenosine monophosphate-activated protein kinase (AMPK) is a key regulator of mammalian energy homeostasis and has been implicated in mediating many of the beneficial effects of exercise and wt. loss including lipid and glucose trafficking. As such, the enzyme has long been of interest as a target for the treatment of Type 2 Diabetes Mellitus. The authors describe the optimization of β1-selective, liver-targeted AMPK activators and their evolution into systemic pan-activators capable of acutely lowering glucose in mouse models. Identifying surrogates for the key acid moiety in early generation compds. proved essential in improving β2-activation and in balancing improvements in plasma unbound fraction while avoiding liver sequestration.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvV2mt77J&md5=c3cc173033071b400200fbed73d91087

     
122. 122

     Myers, R. W.; Guan, H. P.; Ehrhart, J.; Petrov, A.; Prahalada, S.; Tozzo, E.; Yang, X.; Kurtz, M. M.; Trujillo, M.; Gonzalez Trotter, D.; Feng, D.; Xu, S.; Eiermann, G.; Holahan, M. A.; Rubins, D.; Conarello, S.; Niu, X.; Souza, S. C.; Miller, C.; Liu, J.; Lu, K.; Feng, W.; Li, Y.; Painter, R. E.; Milligan, J. A.; He, H.; Liu, F.; Ogawa, A.; Wisniewski, D.; Rohm, R. J.; Wang, L.; Bunzel, M.; Qian, Y.; Zhu, W.; Wang, H.; Bennet, B.; LaFranco Scheuch, L.; Fernandez, G. E.; Li, C.; Klimas, M.; Zhou, G.; van Heek, M.; Biftu, T.; Weber, A.; Kelley, D. E.; Thornberry, N.; Erion, M. D.; Kemp, D. M.; Sebhat, I. K. Systemic Pan-AMPK Activator MK-8722 Improves Glucose Homeostasis but Induces Cardiac Hypertrophy. Science 2017, 357, 507– 511,  DOI: 10.1126/science.aah5582

     [Crossref], [PubMed], [CAS], Google Scholar

     122

     Systemic pan-AMPK activator MK-8722 improves glucose homeostasis but induces cardiac hypertrophy

     Myers, Robert W.; Guan, Hong-Ping; Ehrhart, Juliann; Petrov, Aleksandr; Prahalada, Srinivasa; Tozzo, Effie; Yang, Xiaodong; Kurtz, Marc M.; Trujillo, Maria; Gonzalez Trotter, Dinko; Feng, Danqing; Xu, Shiyao; Eiermann, George; Holahan, Marie A.; Rubins, Daniel; Conarello, Stacey; Niu, Xiaoda; Souza, Sandra C.; Miller, Corin; Liu, Jinqi; Lu, Ku; Feng, Wen; Li, Ying; Painter, Ronald E.; Milligan, James A.; He, Huaibing; Liu, Franklin; Ogawa, Aimie; Wisniewski, Douglas; Rohm, Rory J.; Wang, Liyang; Bunzel, Michelle; Qian, Ying; Zhu, Wei; Wang, Hongwu; Bennet, Bindu; La Franco Scheuch, Lisa; Fernandez, Guillermo E.; Li, Cai; Klimas, Michael; Zhou, Gaochao; van Heek, Margaret; Biftu, Tesfaye; Weber, Ann; Kelley, David E.; Thornberry, Nancy; Erion, Mark D.; Kemp, Daniel M.; Sebhat, Iyassu K.

     Science (Washington, DC, United States) (2017), 357 (6350), 507-511CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)

     5'-Adenosine monophosphate-activated protein kinase (AMPK) is a master regulator of energy homeostasis in eukaryotes. Despite three decades of investigation, the biol. roles of AMPK and its potential as a drug target remain incompletely understood, largely because of a lack of optimized pharmacol. tools. We developed MK-8722, a potent, direct, allosteric activator of all 12 mammalian AMPK complexes. In rodents and rhesus monkeys, MK-8722-mediated AMPK activation in skeletal muscle induced robust, durable, insulin-independent glucose uptake and glycogen synthesis, with resultant improvements in glycemia and no evidence of hypoglycemia. These effects translated across species, including diabetic rhesus monkeys, but manifested with concomitant cardiac hypertrophy and increased cardiac glycogen without apparent functional sequelae.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXht1GgsrfO&md5=9dcb25412cf382cb3e1c8908a467f4b1

     
123. 123

     Bolze, S.; Hallakou-Bozec, S.; Roden, M.; Roux, J. PXL770, A Novel Direct Ampk Activator, Improves Metabolic Disorders in a Diet-Induced Mice Model of Obesity and Diabetes. Presented at the 52nd Annual Meeting of the European Association for the Study of Diabetes, Munich, Germany, September 12–16, 2016, Oral Presentation #113.

     Google Scholar

     There is no corresponding record for this reference.

     
124. 124

     Gluais-Dagorn, P., Fouqueray, P.; Bolze, S.; Hallakou-Bozec, S. PXL770, a New Direct AMP Kinase Activator, Demonstrates Promising Effects for Treatment of Non-Alcoholic Steatohepatitis. Presented at the Global NASH Congress, London, UK, February 26–27, 2018, Poster #4.

     Google Scholar

     There is no corresponding record for this reference.

     
125. 125

     Cravo, D.; Hallakou-Bozec, S.; Bolze, S.; Lepifre, F.; Faveriel, L. Thienopyridone Dervatives Useful as Activators of AMPK. WO2014001554, 2014.

     Google Scholar

     There is no corresponding record for this reference.

     
126. 126

     Cravo, D.; Hallakou-Bozec, S.; Bolze, S.; Lepifre, F. Thieno[2,3-b]pyidinedione Activators of AMPK and Therapeutic Uses Thereof. International Patent WO2011080277, 2011.

     Google Scholar

     There is no corresponding record for this reference.

     
127. 127

     Wakil, S. J.; Abu-Elheiga, L. A. Fatty Acid Metabolism: Target for Metabolic Syndrome. J. Lipid Res. 2009, 50 (Suppl), S138– 143,  DOI: 10.1194/jlr.R800079-JLR200

     [Crossref], [PubMed], [CAS], Google Scholar

     127

     Fatty acid metabolism: target for metabolic syndrome

     Wakil Salih J; Abu-Elheiga Lutfi A

     Journal of lipid research (2009), 50 Suppl (), S138-43 ISSN:0022-2275.

     Fatty acids are a major energy source and important constituents of membrane lipids, and they serve as cellular signaling molecules that play an important role in the etiology of the metabolic syndrome. Acetyl-CoA carboxylases 1 and 2 (ACC1 and ACC2) catalyze the synthesis of malonyl-CoA, the substrate for fatty acid synthesis and the regulator of fatty acid oxidation. They are highly regulated and play important roles in the energy metabolism of fatty acids in animals, including humans. They are presently considered as an attractive target to regulate the human diseases of obesity, diabetes, cancer, and cardiovascular complications. In this review we discuss the role of fatty acid metabolism and its key players, ACC1 and ACC2, in animal evolution and physiology, as related to health and disease.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1MzltFGrtw%253D%253D&md5=ab56fd3a5b654059392027d83e6bdde3

     
128. 128

     Saggerson, D. Malonyl-CoA, a Key Signaling Molecule in Mammalian Cells. Annu. Rev. Nutr. 2008, 28, 253– 272,  DOI: 10.1146/annurev.nutr.28.061807.155434

     [Crossref], [PubMed], [CAS], Google Scholar

     128

     Malonyl-CoA, a key signaling molecule in mammalian cells

     Saggerson, David

     Annual Review of Nutrition (2008), 28 (), 253-272, 3 platesCODEN: ARNTD8; ISSN:0199-9885. (Annual Reviews Inc.)

     A review. Malonyl-CoA can be formed within mitochondria, peroxisomes, and cytosol of mammalian cells. In addn. to being an intermediate in the pathways of de novo fatty acid biosynthesis and fatty acid elongation, malonyl-CoA has an important signaling function through its allosteric inhibition of carnitine palmitoyltransferase 1, the enzyme that normally exerts flux control over mitochondrial β-oxidn. Malonyl-CoA is rapidly turned over in mammalian cells, and the activities of acetyl-CoA carboxylase and malonyl-CoA decarboxylase are important determinants of its cytosolic concn. It is now recognized that malonyl-CoA participates in a diverse range of physiol. or pathol. responses and systems. These include the ketogenic response of the liver to fasting and diabetes, carbohydrate vs. fat fuel selection in muscle tissues, metabolic changes in muscle during contraction, alterations in fatty acid metab. during cardiac ischemia and postischemic reperfusion, stimulation of B cell insulin secretion by glucose, and the hypothalamic control of appetite.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhtV2isLzK&md5=5c99eac0f1d0dfd484c7a98f19c0144e

     
129. 129

     Kim, K. H. Regulation of Mammalian Acetyl-Coenzyme a Carboxylase. Annu. Rev. Nutr. 1997, 17, 77– 99,  DOI: 10.1146/annurev.nutr.17.1.77

     [Crossref], [PubMed], [CAS], Google Scholar

     129

     Regulation of mammalian acetyl-coenzyme A carboxylase

     Kim, Ki-Han

     Annual Review of Nutrition (1997), 17 (), 77-99CODEN: ARNTD8; ISSN:0199-9885. (Annual Reviews)

     A review with 107 refs. Long-chain fatty acids are involved in all aspects of cellular structure and function. For controlling amts. of fatty acids, cells are endowed with two acetylCoA carboxylase (ACC) systems. ACC-α is the rate-limiting enzyme in the biogenesis of long-chain fatty acids, and ACC-β is believed to control mitochondrial fatty acid oxidn. These two isoforms of ACC control the amt. of fatty acids in the cells. Phosphorylation and dephosphorylation of ACC-α cause enzyme inactivation and activation, resp., and serve as the enzyme's short-term regulatory mechanism. Covalently modified enzymes become more sensitive toward cellular metabolites. In addn., many hormones and nutrients affect gene expression. The gene products formed are heterogeneous and tissue specific. The ACC-β gene is located on human chromosome 12; the cDNA for this gene has just been cloned. The gene for the α-isoform is located on human chromosome 17. The catalytic core of the β-isoform is homologous to that of the α-isoform, except for an addnl. peptide of about 150 amino acids at the N terminus. This extra peptide sequence makes the β-form about 10,000 daltons larger, and it is thought to be involved in the unique role that has been assigned to this enzyme. The detailed control mechanisms for the β-isoform are not known.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXkvFGmt78%253D&md5=a4b97c242796e71c8242ed38c26b4849

     
130. 130

     Nishiura, Y.; Matsumura, A.; Kobayashi, N.; Shimazaki, A.; Sakamoto, S.; Kitade, N.; Tonomura, Y.; Ino, A.; Okuno, T. Discovery of a Novel Olefin Derivative As a Highly Potent and Selective Acetyl-CoA Carboxylase 2 Inhibitor with In Vivo Efficacy. Bioorg. Med. Chem. Lett. 2018, 28, 2498– 2503,  DOI: 10.1016/j.bmcl.2018.05.055

     [Crossref], [PubMed], [CAS], Google Scholar

     130

     Discovery of a novel olefin derivative as a highly potent and selective acetyl-CoA carboxylase 2 inhibitor with in vivo efficacy

     Nishiura, Yuji; Matsumura, Akira; Kobayashi, Naotake; Shimazaki, Atsuyuki; Sakamoto, Shingo; Kitade, Naohisa; Tonomura, Yutaka; Ino, Akira; Okuno, Takayuki

     Bioorganic & Medicinal Chemistry Letters (2018), 28 (14), 2498-2503CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)

     Novel acetyl-CoA carboxylase 2 (ACC2) selective inhibitors were identified by the conversion of the alkyne unit of A-908292 to the olefin linker. Modification of the center and left part of the lead compd. I improved the ACC2 inhibitory activity and CYP450 inhibition profile, and afforded a highly selective ACC2 inhibitor II which showed in vivo efficacy in C57BL/6 mice.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtFemsLrL&md5=ceddcbb845e59807c27398d134e57f94

     
131. 131

     Mizojiri, R.; Asano, M.; Tomita, D.; Banno, H.; Nii, N.; Sasaki, M.; Sumi, H.; Satoh, Y.; Yamamoto, Y.; Moriya, T.; Satomi, Y.; Maezaki, H. Discovery of Novel Selective Acetyl-CoA Carboxylase (ACC) 1 Inhibitors. J. Med. Chem. 2018, 61, 1098– 1117,  DOI: 10.1021/acs.jmedchem.7b01547

     [ACS Full Text ], [CAS], Google Scholar

     131

     Discovery of Novel Selective Acetyl-CoA Carboxylase (ACC) 1 Inhibitors

     Mizojiri, Ryo; Asano, Moriteru; Tomita, Daisuke; Banno, Hiroshi; Nii, Noriyuki; Sasaki, Masako; Sumi, Hiroyuki; Satoh, Yoshihiko; Yamamoto, Yukiko; Moriya, Takeo; Satomi, Yoshinori; Maezaki, Hironobu

     Journal of Medicinal Chemistry (2018), 61 (3), 1098-1117CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

     The authors initiated structure-activity relationship (SAR) studies for selective ACC1 inhibitors from 1a (N-(1-(2-(3-(3-methylphenoxy)azetidin-1-yl)-1,3-benzoxazol-6-yl)ethyl)acetamide) as a lead compd. SAR studies of bicyclic scaffolds revealed many potent and selective ACC1 inhibitors represented by 1f (N-(1-(2-(4-(3-(Cyclopropylmethoxy)phenoxy)phenyl)-1,3-benzoxazol-6-yl)ethyl)acetamide), however most of them had physicochem. issues, particularly low aq. soly. and potent CYP inhibition. To address these two issues and improve the drug-likeness of this chem. series, the authors converted the bicyclic scaffold into a monocyclic framework. Ultimately, this lead the authors to discover a novel monocyclic deriv. 1q (1-((2S)-1-((2-(4-(3-(Cyclopropylmethoxy)phenoxy)phenyl)-1,3-oxazol-5-yl)oxy)propan-2-yl)urea) as a selective ACC1 inhibitor, which showed highly potent and selective ACC1 inhibition as well as acceptable soly. and CYP inhibition profiles. Since compd. 1q displayed favorable bioavailability in mouse cassette dosing testing, the authors conducted in vivo PD studies of this compd. Oral administration of 1q significantly reduced the concn. of malonyl-CoA in HCT-116 xenograft tumors at doses of more than 30 mg/kg. Accordingly, the authors' novel series of selective ACC1 inhibitors represents a set of useful orally-available research tools, as well as potential therapeutic agents for cancer and fatty acid related diseases.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvFKit7%252FN&md5=a049fac3bc1a4df382cfd73cc8b6c488

     
132. 132

     Clark, R. F.; Zhang, T.; Wang, X.; Wang, R.; Zhang, X.; Camp, H. S.; Beutel, B. A.; Sham, H. L.; Gu, Y. G. Phenoxy Thiazole Derivatives as Potent and Selective Acetyl-CoA Carboxylase 2 Inhibitors: Modulation of Isozyme Selectivity by Incorporation of Phenyl Ring Substituents. Bioorg. Med. Chem. Lett. 2007, 17, 1961– 1965,  DOI: 10.1016/j.bmcl.2007.01.022

     [Crossref], [PubMed], [CAS], Google Scholar

     132

     Phenoxy thiazole derivatives as potent and selective acetyl-CoA carboxylase 2 inhibitors: Modulation of isozyme selectivity by incorporation of phenyl ring substituents

     Clark, Richard F.; Zhang, Tianyuan; Wang, Xiaojun; Wang, Rongqi; Zhang, Xiaolin; Camp, Heidi S.; Beutel, Bruce A.; Sham, Hing L.; Gu, Yu Gui

     Bioorganic & Medicinal Chemistry Letters (2007), 17 (7), 1961-1965CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Ltd.)

     A Ph ring substitution strategy was employed to optimize the ACC2 potency and selectivity profiles of a recently discovered phenoxy thiazolyl series of acetyl-CoA carboxylase inhibitors. Ring substituents were shown to dramatically affect isoenzyme selectivity. Modifications that generally impart high levels of ACC2 selectivity (>3000-fold) while maintaining excellent ACC2 potency (IC50s ∼ 9-20 nM) were identified.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXis1Onsrs%253D&md5=356c09befc245b7fa54b0233d6560961

     
133. 133

     Gu, Y. G.; Weitzberg, M.; Clark, R. F.; Xu, X.; Li, Q.; Zhang, T.; Hansen, T. M.; Liu, G.; Xin, Z.; Wang, X.; Wang, R.; McNally, T.; Camp, H. S.; Beutel, B. A.; Sham, H. L. Synthesis and Structure-Activity Relationships of N-{3-[2-(4-alkoxyphenoxy)thiazol-5-yl]-1- methylprop-2-ynyl}carboxy Derivatives As Selective Acetyl-CoA Carboxylase 2 Inhibitors. J. Med. Chem. 2006, 49, 3770– 3773,  DOI: 10.1021/jm060484v

     [ACS Full Text ], [CAS], Google Scholar

     133

     Synthesis and Structure-Activity Relationships of N-{3-[2-(4-Alkoxyphenoxy)thiazol-5-yl]-1- methylprop-2-ynyl}carboxy Derivatives as Selective Acetyl-CoA Carboxylase 2 Inhibitors

     Gu, Yu Gui; Weitzberg, Moshe; Clark, Richard F.; Xu, Xiangdong; Li, Qun; Zhang, Tianyuan; Hansen, T. Matthew; Liu, Gang; Xin, Zhili; Wang, Xiaojun; Wang, Rongqi; McNally, Teresa; Camp, Heidi; Beutel, Bruce A.; Sham, Hing L.

     Journal of Medicinal Chemistry (2006), 49 (13), 3770-3773CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

     Substituted phenylthio- and phenoxythiazolylpropynylamine derivs. (and a phenoxythiazolylpropynol) such as I are prepd. as selective inhibitors of human acetyl CoA carboxylase 2 (hACC 2) over human acetyl CoA carboxylase 1 (hACC 1). Cyclocondensation of phenols and benzenethiols with 2,5-dibromothiazole, Sonogashira coupling with substituted N-propargylphthalimides, deprotection and cleavage provide the title compds. I inhibits hACC2 and hACC1 with IC50 values of 0.038 μM and > 30 μM, resp. Isopropoxyphenoxyphenylbutynylacetamide II acts as a dual hACC1/hACC2 inhibitor, with IC50 values of 0.006 μM and 0.029 μM against hACC2 and hACC1, resp. I decreases the amts. of malonyl CoA in rat muscle and liver when given orally. The pharmacokinetics of racemic I in rats is detd.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XltlKksLc%253D&md5=e9f4e0ef363cc39bf822b9374d28534f

     
134. 134

     Savage, D. B.; Petersen, K. F.; Shulman, G. I. Disordered Lipid Metabolism and the Pathogenesis of Insulin Resistance. Physiol. Rev. 2007, 87, 507– 520,  DOI: 10.1152/physrev.00024.2006

     [Crossref], [PubMed], [CAS], Google Scholar

     134

     Disordered lipid metabolism and the pathogenesis of insulin resistance

     Savage, David B.; Petersen, Kitt Falk; Shulman, Gerald I.

     Physiological Reviews (2007), 87 (2), 507-520CODEN: PHREA7; ISSN:0031-9333. (American Physiological Society)

     A review. Although abnormal glucose metab. defines type 2 diabetes mellitus (T2DM) and accounts for many of its symptoms and complications, efforts to understand the pathogenesis of T2DM are increasingly focused on disordered lipid metab. Here we review recent human studies exploring the mechanistic links between disorders of fatty acid/lipid metab. and insulin resistance. As "mouse models of insulin resistance" were comprehensively reviewed in Physiol. Reviews by Nandi et al. in 2004, we will conc. on human studies involving the use of isotopes and/or magnetic resonance spectroscopy, occasionally drawing on mouse models which provide addnl. mechanistic insight.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXoslGmu7Y%253D&md5=2a7234646d5e6c0a639f4bb089405ab2

     
135. 135

     Samuel, V. T.; Petersen, K. F.; Shulman, G. I. Lipid-Induced Insulin Resistance: Unravelling the Mechanism. Lancet 2010, 375, 2267– 2277,  DOI: 10.1016/S0140-6736(10)60408-4

     [Crossref], [PubMed], [CAS], Google Scholar

     135

     Lipid-induced insulin resistance: unravelling the mechanism

     Samuel, Varman T.; Petersen, Kitt Falk; Shulman, Gerald I.

     Lancet (2010), 375 (9733), 2267-2277CODEN: LANCAO; ISSN:0140-6736. (Elsevier Ltd.)

     A review. Insulin resistance has long been assocd. with obesity. More than 40 years ago, Randle and colleagues postulated that lipids impaired insulin-stimulated glucose use by muscles through inhibition of glycolysis at key points. However, work over the past two decades has shown that lipid-induced insulin resistance in skeletal muscle stems from defects in insulin-stimulated glucose transport activity. The steatitic liver is also resistant to insulin in terms of inhibition of hepatic glucose prodn. and stimulation of glycogen synthesis. In muscle and liver, the intracellular accumulation of lipids-namely, diacylglycerol-triggers activation of novel protein kinases C with subsequent impairments in insulin signalling. This unifying hypothesis accounts for the mechanism of insulin resistance in obesity, type 2 diabetes, lipodystrophy, and ageing; and the insulin-sensitizing effects of thiazolidinediones.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXotVagtrk%253D&md5=44fd5cf01e603508d38021ec5e86becf

     
136. 136

     Imai, N.; Cohen, D. E. Trimming the Fat: Acetyl-CoA Carboxylase Inhibition for the Management of NAFLD. Hepatology 2018, 68, 2062– 2065,  DOI: 10.1002/hep.30206

     [Crossref], [PubMed], [CAS], Google Scholar

     136

     Trimming the Fat: Acetyl-CoA Carboxylase Inhibition for the Management of NAFLD

     Imai Norihiro; Cohen David E

     Hepatology (Baltimore, Md.) (2018), 68 (6), 2062-2065 ISSN:.

     There is no expanded citation for this reference.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3c7ltVSksg%253D%253D&md5=292cc25b2466089f31288ac006590717

     
137. 137

     Kim, C. W.; Addy, C.; Kusunoki, J.; Anderson, N. N.; Deja, S.; Fu, X.; Burgess, S. C.; Li, C.; Ruddy, M.; Chakravarthy, M.; Previs, S.; Milstein, S.; Fitzgerald, K.; Kelley, D. E.; Horton, J. D. Acetyl CoA Carboxylase Inhibition Reduces Hepatic Steatosis but Elevates Plasma Triglycerides in Mice and Humans: A Bedside to Bench Investigation. Cell Metab. 2017, 26, 394– 406,  DOI: 10.1016/j.cmet.2017.07.009

     [Crossref], [PubMed], [CAS], Google Scholar

     137

     Acetyl CoA Carboxylase Inhibition Reduces Hepatic Steatosis but Elevates Plasma Triglycerides in Mice and Humans: A Bedside to Bench Investigation

     Kim, Chai-Wan; Addy, Carol; Kusunoki, Jun; Anderson, Norma N.; Deja, Stanislaw; Fu, Xiaorong; Burgess, Shawn C.; Li, Cai; Chakravarthy, Manu; Previs, Steve; Milstein, Stuart; Fitzgerald, Kevin; Kelley, David E.; Horton, Jay D.

     Cell Metabolism (2017), 26 (2), 394-406.e6CODEN: CMEEB5; ISSN:1550-4131. (Elsevier Inc.)

     Inhibiting lipogenesis prevents hepatic steatosis in rodents with insulin resistance. To det. if reducing lipogenesis functions similarly in humans, we developed MK-4074, a liver-specific inhibitor of acetyl-CoA carboxylase (ACC1) and (ACC2), enzymes that produce malonyl-CoA for fatty acid synthesis. MK-4074 administered to subjects with hepatic steatosis for 1 mo lowered lipogenesis, increased ketones, and reduced liver triglycerides by 36%. Unexpectedly, MK-4074 increased plasma triglycerides by 200%. To further investigate, mice that lack ACC1 and ACC2 in hepatocytes (ACC dLKO) were generated. Deletion of ACCs decreased polyunsatd. fatty acid (PUFA) concns. in liver due to reduced malonyl-CoA, which is required for elongation of essential fatty acids. PUFA deficiency induced SREBP-1c, which increased GPAT1 expression and VLDL secretion. PUFA supplementation or siRNA-mediated knockdown of GPAT1 normalized plasma triglycerides. Thus, inhibiting lipogenesis in humans reduced hepatic steatosis, but inhibiting ACC resulted in hypertriglyceridemia due to activation of SREBP-1c and increased VLDL secretion.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXht1Oiur3K&md5=2e263600fbef46f8ca7d2c93e27e1835

     
138. 138

     Harriman, G.; Greenwood, J.; Bhat, S.; Huang, X.; Wang, R.; Paul, D.; Tong, L.; Saha, A. K.; Westlin, W. F.; Kapeller, R.; Harwood, H. J., Jr. Acetyl-CoA Carboxylase Inhibition by ND-630 Reduces Hepatic Steatosis, Improves Insulin Sensitivity, and Modulates Dyslipidemia in Rats. Proc. Natl. Acad. Sci. U. S. A. 2016, 113, E1796– 1805,  DOI: 10.1073/pnas.1520686113

     [Crossref], [PubMed], [CAS], Google Scholar

     138

     Acetyl-CoA carboxylase inhibition by ND-630 reduces hepatic steatosis, improves insulin sensitivity, and modulates dyslipidemia in rats

     Harriman, Geraldine; Greenwood, Jeremy; Bhat, Sathesh; Huang, Xinyi; Wang, Ruiying; Paul, Debamita; Tong, Liang; Saha, Asish K.; Westlin, William F.; Kapeller, Rosana; James Harwood, H.

     Proceedings of the National Academy of Sciences of the United States of America (2016), 113 (13), E1796-E1805CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)

     Simultaneous inhibition of the acetyl-CoA carboxylase (ACC) isoenzymes ACC1 and ACC2 results in concomitant inhibition of fatty acid synthesis and stimulation of fatty acid oxidn. and may favorably affect the morbidity and mortality assocd. with obesity, diabetes, and fatty liver disease. Using structure-based drug design, we have identified a series of potent allosteric protein-protein interaction inhibitors, exemplified by ND-630, that interact within the ACC phosphopeptide acceptor and dimerization site to prevent dimerization and inhibit the enzymic activity of both ACC isoenzymes, reduce fatty acid synthesis and stimulate fatty acid oxidn. in cultured cells and in animals, and exhibit favorable drug-like properties. When administered chronically to rats with diet-induced obesity, ND-630 reduces hepatic steatosis, improves insulin sensitivity, reduces wt. gain without affecting food intake, and favorably affects dyslipidemia. When administered chronically to Zucker diabetic fatty rats, ND-630 reduces hepatic steatosis, improves glucose-stimulated insulin secretion, and reduces Hb A1c (0.9% redn.). Together, these data suggest that ACC inhibition by representatives of this series may be useful in treating a variety of metabolic disorders, including metabolic syndrome, type 2 diabetes mellitus, and fatty liver disease.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XktFemsbo%253D&md5=97760b371a1ccdb18e9afa50780b1066

     
139. 139

     Loomba, R.; Kayali, Z.; Noureddin, M.; Ruane, P.; Lawitz, E. J.; Bennett, M.; Wang, L.; Harting, E.; Tarrant, J. M.; McColgan, B. J.; Chung, C.; Ray, A. S.; Subramanian, G. M.; Myers, R. P.; Middleton, M. S.; Lai, M.; Charlton, M.; Harrison, S. A. GS-0976 Reduces Hepatic Steatosis and Fibrosis Markers in Patients with Nonalcoholic Fatty Liver Disease. Gastroenterology 2018, 155, 1463– 1473,  DOI: 10.1053/j.gastro.2018.07.027

     [Crossref], [PubMed], [CAS], Google Scholar

     139

     GS-0976 Reduces Hepatic Steatosis and Fibrosis Markers in Patients With Nonalcoholic Fatty Liver Disease

     Loomba, Rohit; Kayali, Zeid; Noureddin, Mazen; Ruane, Peter; Lawitz, Eric J.; Bennett, Michael; Wang, Lulu; Harting, Eliza; Tarrant, Jacqueline M.; McColgan, Bryan J.; Chung, Chuhan; Ray, Adrian S.; Subramanian, G. Mani; Myers, Robert P.; Middleton, Michael S.; Lai, Michelle; Charlton, Michael; Harrison, Stephen A.

     Gastroenterology (2018), 155 (5), 1463-1473.e6CODEN: GASTAB; ISSN:0016-5085. (Elsevier)

     De novo lipogenesis is increased in livers of patients with nonalcoholic steatohepatitis (NASH). Acetyl-coenzyme carboxylase catalyzes the rate-limiting step in this process. We evaluated the safety and efficacy of GS-0976, an inhibitor of acetyl-CoA carboxylase in liver, in a phase 2 randomized placebo-controlled trial of patients with NASH. We analyzed data from 126 patients with hepatic steatosis of at least 8%, based on the magnetic resonance imaging-estd. proton d. fat fraction (MRI-PDFF), and liver stiffness of at least 2.5 kPa, based on magnetic resonance elastog. measurement or historical biopsy result consistent with NASH and F1-F3 fibrosis. Patients were randomly assigned (2:2:1) to groups given GS-0976 20 mg, GS-0976 5 mg, or placebo daily for 12 wk, from August 8, 2016 through July 18, 2017. Measures of hepatic steatosis, stiffness, serum markers of fibrosis, and plasma metabolomics were evaluated. The primary aims were to confirm previous findings and evaluate the relation between dose and efficacy. A relative decrease of at least 30% from baseline in MRI-PDFF (PDFF response) occurred in 48% of patients given GS-0976 20 mg (P = .004 vs placebo), 23% given GS-0976 5 mg (P = .43 vs placebo), and 15% given placebo. Median relative decreases in MRI-PDFF were greater in patients given GS-0976 20 mg (decrease of 29%) than those given placebo (decrease of 8%; P = .002). Changes in magnetic resonance elastog.-measured stiffness did not differ among groups, but a dose-dependent decrease in the fibrosis marker tissue inhibitor of metalloproteinase 1 was obsd. in patients given GS-0976 20 mg. Plasma levels of acylcarnitine species also decreased in patients with a PDFF response given GS-0976 20 mg. GS-0976 was safe, but median relative increases of 11% and 13% in serum levels of triglycerides were obsd. in patients given GS-0976. In a randomized placebo-controlled trial of patients with NASH, we found 12-wk administration of GS-0976 20 mg decreased hepatic steatosis, selected markers of fibrosis, and liver biochem. ClinicalTrials.gov ID NCT02856555.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitV2qtb%252FI&md5=8ccf3b86cb8f5d2a194d5049140f2ccd

     
140. 140

     Lawitz, E.; Gane, E.; Ruane, P.; Herring, R.; Younes, Z. H.; Kwo, P.; Zhang, J.; Jia, C.; Chuang, J.; McColgan, B.; Chung, C.; Subramanian, M.; Myers, R.; Middleton, M.; Li, K.; Hellerstein, M.; Noureddin, M.; Harrison, S.; Loomba, R. A Combination of the ACC Inhibitor GS-0976 and the Nonsteroidal FXR Agonist GS-9674 Improves Hepatic Steatosis, Biochemistry, and Stiffness in Patients with Non-Alcoholic Steatohepatitis. Presented at the European Associate for the Study of the Liver International Liver Conference, Vienna, Austria, April 10–14, 2019; SAT-352.

     Google Scholar

     There is no corresponding record for this reference.

     
141. 141

     Didiuk, M. T.; Dow, R. L.; Griffith, D. A. N1-Pyrazolospiroketone Acetyl-CoA Carboxylase Inhibitors. International Patent WO2012042433, 2012.

     Google Scholar

     There is no corresponding record for this reference.

     
142. 142

     Fernando, D.; Lacasse, S. M.; Wiglesworth, K. Crystalline 2-Amino-2-(hydroxymethyl)propane-1,3-diol Salt ff 4-(4-(1-Isopropyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-5,4’-piperidine]-1’-carbonyl)-6-methoxypyridin-2-yl)benzoic Acid. International Patent WO2019102311, 2019.

     Google Scholar

     There is no corresponding record for this reference.

     
143. 143

     Bagley, S. W.; Dow, R. L.; Griffith, D. A.; Smith, A. C. N1/N2-Lactam Acetyl-CoA Carboxylase Inhibitors. International Patent WO2012056372, 2012.

     Google Scholar

     There is no corresponding record for this reference.

     
144. 144

     Novartis - Pfizer Collaboration. https://www.novartis.com/news/media-releases/novartis-announces-clinical-collaboration-pfizer-advance-treatment-nash (accessed Sept 25, 2019).

     Google Scholar

     There is no corresponding record for this reference.

     
145. 145

     Zammit, V. A. Hepatic Triacylglycerol Synthesis and Secretion: DGAT2 as the Link Between Glycaemia and Triglyceridaemia. Biochem. J. 2013, 451, 1– 12,  DOI: 10.1042/BJ20121689

     [Crossref], [PubMed], [CAS], Google Scholar

     145

     Hepatic triacylglycerol synthesis and secretion: DGAT2 as the link between glycaemia and triglyceridaemia

     Zammit, Victor A.

     Biochemical Journal (2013), 451 (1), 1-12CODEN: BIJOAK; ISSN:0264-6021. (Portland Press Ltd.)

     A review. The liver regulates both glycemia and triglyceridemia. Hyperglycemia and hypertriglyceridemia are both characteristic of (pre)diabetes. Recent observations on the specialised role of DGAT2 (diacylglycerol acyltransferase 2) in catalyzing the de novo synthesis of triacylglycerols from newly synthesized fatty acids and nascent diacylglycerols identifies this enzyme as the link between the two. This places DGAT2 at the center of carbohydrate-induced hypertriglyceridemia and hepatic steatosis. This function is complemented, but not substituted for, by the ability of DGAT1 to rescue partial glycerides from complete hydrolysis. In peripheral tissues not normally considered to be lipogenic, synthesis of triacylgycerols may largely bypass DGAT2 except in hyperglycemic/hyperinsulinemic conditions, when induction of de novo fatty acid synthesis in these tissues may contribute towards increased triacylglycerol secretion (intestine) or insulin resistance (adipose tissue, and cardiac and skeletal muscle).

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXjvVKltLw%253D&md5=9f5d5c77b554c32130993f885754b746

     
146. 146

     Subramanian, S.; Chait, A. Hypertriglyceridemia Secondary to Obesity and Diabetes. Biochim. Biophys. Acta, Mol. Cell Biol. Lipids 2012, 1821, 819– 825,  DOI: 10.1016/j.bbalip.2011.10.003

     [Crossref], [CAS], Google Scholar

     146

     Hypertriglyceridemia secondary to obesity and diabetes

     Subramanian, Savitha; Chait, Alan

     Biochimica et Biophysica Acta, Molecular and Cell Biology of Lipids (2012), 1821 (5), 819-825CODEN: BBMLFG; ISSN:1388-1981. (Elsevier B. V.)

     A review. Hypertriglyceridemia is a common lipid abnormality in persons with visceral obesity, metabolic syndrome and type 2 diabetes. Hypertriglyceridemia typically occurs in conjunction with low HDL levels and atherogenic small dense LDL particles and is assocd. with increased cardiovascular risk. Insulin resistance is often an underlying feature and results in increased free fatty acid (FFA) delivery to the liver due to increased peripheral lipolysis. Increased hepatic VLDL prodn. occurs due to increased substrate availability via FFAs, decreased apolipoprotein B100 degrdn. and increased lipogenesis. Postprandial hypertriglyceridemia also is a common feature of insulin resistance. Small dense LDL that coexist with decreased HDL particles in hypertriglyceridemic states are highly pro-atherogenic due to their enhanced endothelial permeability, proteoglycan binding abilities and susceptibility to oxidn. Hypertriglyceridemia also occurs in undertreated individuals with type 1 diabetes but intensive glucose control normalizes lipid abnormalities. However, development of visceral obesity in these patients unravels a similar metabolic profile as in patients with insulin resistance. Modest hypertriglyceridemia increases cardiovascular risk, while marked hypertriglyceridemia should be considered a risk for pancreatitis. Lifestyle modification is an important therapeutic strategy. Drug therapy is primarily focused on lowering LDL levels with statins, since efforts at triglyceride lowering and HDL raising with fibrates and/or niacin have not yet been shown to be beneficial in improving cardiovascular risk. Fibrates, however, are first-line agents when marked hypertriglyceridemia is present. This article is part of a Special Issue entitled Triglyceride Metab. and Disease.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XkslehsL4%253D&md5=43216b523e823ea4c01c2dd2b52aacb9

     
147. 147

     Kennedy, E. P. Metabolism of Lipides. Annu. Rev. Biochem. 1957, 26, 119– 148,  DOI: 10.1146/annurev.bi.26.070157.001003

     [Crossref], [PubMed], [CAS], Google Scholar

     147

     Metabolism of lipides

     Kennedy, Eugene P.

     Annual Review of Biochemistry (1957), 26 (), 119-48CODEN: ARBOAW; ISSN:0066-4154.

     cf. C.A. 50, 15639i. A review covering enzymic oxidation and synthesis of fatty acids; metabolism of short chain and branched chain fatty acids; biosynthesis, catabolism, and metabolic functions of phospholipides; and the structure of native plasmalogen. 225 references.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaG2sXhtVSgt7o%253D&md5=5ec03e799d5953c585020fcd89864f58

     
148. 148

     Kayden, H. J.; Senior, J. R.; Mattson, F. H. The Monoglyceride Pathway of Fat Absorption in Man. J. Clin. Invest. 1967, 46, 1695– 1703,  DOI: 10.1172/JCI105660

     [Crossref], [PubMed], [CAS], Google Scholar

     148

     Monoglyceride pathway of fat absorption in man

     Kayden, Herbert J.; Senior, John R.; Mattson, Fred H.

     Journal of Clinical Investigation (1967), 46 (11), 1695-703CODEN: JCINAO; ISSN:0021-9738.

     The absorption of fat was studied in 5 male subjects with accumulation of the thoracic duct in the neck by the administration of doubly labeled monoglycerides or triglycerides and labeled free glycerol or labeled free oleic acid by gastric or duodenal intubation. Total recovery of the administered glyceride radioactivity from the lymph lipids ranged from 35-53% for the glycerol label (3H) and from 35-57% of the fatty acid label (14C). The recovery of administered radioactive free glycerol in lymph lipids was only 4.1% even when given in mixt. with bile salts, fatty acids, and monoglycerides. A comparison of the isotope ratios of the 2 components (glycerol and fatty acid) of the lymph glycericdes with the ratios of these components of the original meal glyceride showed little change during the initial period of fat absorption, indicating that the doubly labeled monoglycerides passed into the lymph intact. During the later part of the period of major fat absorption, the ratios in lymph lipids changed due to the loss of glycerol representation indicating monoglyceride hydrolysis and portal venous diversion of free glycerol. Confirmation of the intact nature of 2-monoglyceride during absorption was made by analyzing the amt. and position of the labeled fatty acid in the lymph triglycerides. The percentage of labeled fatty acid in the various positions of the lymph triglycerides was identical with that of the meal during the initial period of fat absorption and then changed, reflecting isomerization of fatty acids and subsequent complete hydrolysis of the glycerides. The 2-monoglyceride pathway appears to be the major route of fat absorption for man during normal digestion and absorption of dietary triglyceride.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF1cXitVahuw%253D%253D&md5=2eb0ddbf1a0f89b745427c99ec1164ba

     
149. 149

     Shi, Y.; Cheng, D. Beyond Triglyceride Synthesis: The Dynamic Functional Roles of MGAT and DGAT Enzymes in Energy Metabolism. Am. J. Physiol. Endocrinol. Metab. 2009, 297, E10– 18,  DOI: 10.1152/ajpendo.90949.2008

     [Crossref], [PubMed], [CAS], Google Scholar

     149

     Beyond triglyceride synthesis: the dynamic functional roles of MGAT and DGAT enzymes in energy metabolism

     Shi, Yuguang; Cheng, Dong

     American Journal of Physiology (2009), 297 (1, Pt. 1), E10-E18CODEN: AJPHAP; ISSN:0002-9513. (American Physiological Society)

     A review. Monoacylglycerol acyltransferases (MGATs) and diacylglycerol acyltransferases (DGATs) catalyze 2 consecutive steps of enzyme reactions in the synthesis of triacylglycerols (TAGs/triglycerides). The metabolic complexity of TAG synthesis is reflected by the presence of multiple isoforms of MGAT and DGAT that differ in catalytic properties, subcellular localization, tissue distribution, and physiol. functions. MGAT and DGAT play fundamental roles in the metab. of monoacylglycerol (MAG), diacylglycerol (DAG), and triacylglycerol (TAG) that are involved in many aspects of physiol. functions, such as intestinal fat absorption, lipoprotein assembly, adipose tissue formation, signal transduction, satiety, and lactation. The recent progress in the phenotypic characterization of mice deficient in MGAT and DGAT and the development of chem. inhibitors have revealed important roles of these enzymes in the regulation of energy homeostasis and insulin sensitivity. Consequently, selective inhibition of MGAT or DGAT by synthetic compds. may provide novel treatment for obesity and its related metabolic complications.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXovVKjtrw%253D&md5=3e68aca351f12d9014e1347dd74e6671

     
150. 150

     Yen, C. L.; Stone, S. J.; Koliwad, S.; Harris, C.; Farese, R. V., Jr. Thematic Review Series: Glycerolipids. DGAT Enzymes and Triacylglycerol Biosynthesis. J. Lipid Res. 2008, 49, 2283– 2301,  DOI: 10.1194/jlr.R800018-JLR200

     [Crossref], [PubMed], [CAS], Google Scholar

     150

     DGAT enzymes and triacylglycerol biosynthesis

     Yen, Chi-Liang Eric; Stone, Scot J.; Koliwad, Suneil; Harris, Charles; Farese, Robert V., Jr.

     Journal of Lipid Research (2008), 49 (11), 2283-2301CODEN: JLPRAW; ISSN:0022-2275. (American Society for Biochemistry and Molecular Biology, Inc.)

     A review. Triacylglycerols (triglycerides; TGs) are the major storage mols. of metabolic energy and fatty acids in most living organisms. Excessive accumulation of TGs, however, is assocd. with human diseases, such as obesity, diabetes mellitus, and steatohepatitis. The final and the only committed step in the biosynthesis of TGs is catalyzed by diacylglycerol acyltransferase (DGAT) enzymes. The genes encoding 2 DGATs, DGAT1 and DGAT2, were identified in the past decade, and the use of mol. tools, including mice deficient in either enzyme, has shed light on their functions. Although DGATs are involved in TG biosynthesis, they have distinct protein sequences and differ in their biochem., cellular, and physiol. functions. Both enzymes may be useful as therapeutic targets for diseases. Here, the authors review the current knowledge of DGATs, focusing on new advances since the cloning of their genes, including possible roles in human health and diseases.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXht12it7rI&md5=166aa21829f49e0e8a736f3e8173b6fe

     
151. 151

     Cases, S.; Smith, S. J.; Zheng, Y. W.; Myers, H. M.; Lear, S. R.; Sande, E.; Novak, S.; Collins, C.; Welch, C. B.; Lusis, A. J.; Erickson, S. K.; Farese, R. V., Jr Identification of a Gene Encoding an Acyl CoA:Diacylglycerol Acyltransferase, a Key Enzyme in Triacylglycerol Synthesis. Proc. Natl. Acad. Sci. U. S. A. 1998, 95, 13018– 13023,  DOI: 10.1073/pnas.95.22.13018

     [Crossref], [PubMed], [CAS], Google Scholar

     151

     Identification of a gene encoding an acyl CoA:diacylglycerol acyltransferase, a key enzyme in triacylglycerol synthesis

     Cases, Sylvaine; Smith, Steven J.; Zheng, Yao-Wu; Myers, Heather M.; Lear, Steven R.; Sande, Eric; Novak, Sabine; Collins, Colin; Welch, Carrie B.; Lusis, Aldons J.; Erickson, Sandra K.; Farese, Robert V., Jr.

     Proceedings of the National Academy of Sciences of the United States of America (1998), 95 (22), 13018-13023CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)

     Triacylglycerols are quant. the most important storage form of energy for eukaryotic cells. Acyl CoA:diacylglycerol acyltransferase (DGAT, EC 2.3.1.20) catalyzes the terminal and only committed step in triacylglycerol synthesis, by using diacylglycerol and fatty acyl CoA as substrates. DGAT plays a fundamental role in the metab. of cellular diacylglycerol and is important in higher eukaryotes for physiol. processes involving triacylglycerol metab. such as intestinal fat absorption, lipoprotein assembly, adipose tissue formation, and lactation. DGAT is an integral membrane protein that has never been purified to homogeneity, nor has its gene been cloned. We identified an expressed sequence tag clone that shared regions of similarity with acyl CoA:cholesterol acyltransferase, an enzyme that also uses fatty acyl CoA as a substrate. Expression of a mouse cDNA for this expressed sequence tag in insect cells resulted in high levels of DGAT activity in cell membranes. No other acyltransferase activity was detected when a variety of substrates, including cholesterol, were used as acyl acceptors. The gene was expressed in all tissues examd.; during differentiation of NIH 3T3-L1 cells into adipocytes, its expression increased markedly in parallel with increases in DGAT activity. The identification of this cDNA encoding a DGAT will greatly facilitate studies of cellular glycerolipid metab. and its regulation.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXntFWktbg%253D&md5=105ec3f7d950fdca7d03f0edd2df3de5

     
152. 152

     Cases, S.; Stone, S. J.; Zhou, P.; Yen, E.; Tow, B.; Lardizabal, K. D.; Voelker, T.; Farese, R. V., Jr. Cloning of DGAT2, A Second Mammalian Diacylglycerol Acyltransferase, and Related Family Members. J. Biol. Chem. 2001, 276, 38870– 38876,  DOI: 10.1074/jbc.M106219200

     [Crossref], [PubMed], [CAS], Google Scholar

     152

     Cloning of DGAT2, a second mammalian diacylglycerol acyltransferase, and related family members

     Cases, Sylvaine; Stone, Scot J.; Zhou, Ping; Yen, Eric; Tow, Bryan; Lardizabal, Kathryn D.; Voelker, Toni; Farese, Robert V., Jr.

     Journal of Biological Chemistry (2001), 276 (42), 38870-38876CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)

     Studies involving the cloning and disruption of the gene for acyl-CoA:diacylglycerol acyltransferase (DGAT) have shown that alternative mechanisms exist for triglyceride synthesis. In this study, we cloned and characterized a second mammalian DGAT, DGAT2, which was identified by its homol. to a DGAT in the fungus Mortierella rammaniana. DGAT2 is a member of a gene family that has no homol. with DGAT1 and includes several mouse and human homologues that are candidates for addnl. DGAT genes. The expression of DGAT2 in insect cells stimulated triglyceride synthesis 6-fold in assays with cellular membranes, and DGAT2 activity was dependent on the presence of fatty acyl-CoA and diacylglycerol, indicating that this protein is a DGAT. Activity was not obsd. for acyl acceptors other than diacylglycerol. DGAT2 activity was inhibited by a high concn. (100 mM) of MgCl2 in an in vitro assay, a characteristic that distinguishes DGAT2 from DGAT1. DGAT2 is expressed in many tissues with high expression levels in the liver and white adipose tissue, suggesting that it may play a significant role in mammalian triglyceride metab.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXnvVenur8%253D&md5=37500f2df99012218adfd4f2ab412d55

     
153. 153

     Lardizabal, K. D.; Mai, J. T.; Wagner, N. W.; Wyrick, A.; Voelker, T.; Hawkins, D. J. DGAT2 is a New Diacylglycerol Acyltransferase Gene Family: Purification, Cloning, and Expression in Insect Cells of Two Polypeptides from Mortierella Ramanniana with Diacylglycerol Acyltransferase Activity. J. Biol. Chem. 2001, 276, 38862– 38869,  DOI: 10.1074/jbc.M106168200

     [Crossref], [PubMed], [CAS], Google Scholar

     153

     DGAT2 is a new diacylglycerol acyltransferase gene family: purification, cloning, and expression in insect cells of two polypeptides from Mortierella ramanniana with diacylglycerol acyltransferase activity

     Lardizabal, Kathryn D.; Mai, Jennifer T.; Wagner, Nicholas W.; Wyrick, Annette; Voelker, Toni; Hawkins, Deborah J.

     Journal of Biological Chemistry (2001), 276 (42), 38862-38869CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)

     Acyl CoA:diacylgycerol acyltransferase (EC 2.3.1.20; DGAT) catalyzes the final step in the prodn. of triacylglycerol. Two polypeptides, which co-purified with DGAT activity, were isolated from the lipid bodies of the oleaginous fungus Mortierella ramanniana with a procedure consisting of dye affinity, hydroxyapatite affinity, and heparin chromatog. The two enzymes had mol. masses of 36 and 36.5 kDa, as estd. by gel electrophoresis, and showed a broad activity max. between pH 6 and 8. Based on partial peptide sequence information, polymerase chain reaction techniques were used to obtain full-length cDNA sequences encoding the purified proteins. Expression of the cDNAs in insect cells conferred high levels of DGAT activity on the membranes isolated from these cells. The two proteins share 54% homol. with each other but are unrelated to the previously identified DGAT gene family (designated DGAT1), which is related to the acyl CoA:cholesterol acyltransferase gene family, or to any other gene family with ascribed function. This report identifies a new gene family, including members in fungi, plants and animals, which encode enzymes with DGAT function. To distinguish the two unrelated families we designate this new class DGAT2 and refer to the M. ramanniana genes as MrDGAT2A and MrDGAT2B.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXnvVenur4%253D&md5=183def6a495418031cd90f2939d29b74

     
154. 154

     Chen, H. C.; Farese, R. V., Jr. Inhibition of Triglyceride Synthesis as a Treatment Strategy for Obesity: Lessons From DGAT1-Deficient Mice. Arterioscler., Thromb., Vasc. Biol. 2005, 25, 482– 486,  DOI: 10.1161/01.ATV.0000151874.81059.ad

     [Crossref], [PubMed], [CAS], Google Scholar

     154

     Inhibition of triglyceride synthesis as a treatment strategy for obesity

     Chen, Hubert C.; Farese, Robert V.

     Arteriosclerosis, Thrombosis, and Vascular Biology (2005), 25 (3), 482-486CODEN: ATVBFA; ISSN:1079-5642. (Lippincott Williams & Wilkins)

     Because the ability to make triglycerides is essential for the accumulation of adipose tissue, inhibition of triglyceride synthesis may ameliorate obesity and its related medical consequences. Acyl CoA:diacylglycerol acyltransferase 1 (DGAT1) is 1 of 2 DGAT enzymes that catalyze the final reaction in the known pathways of mammalian triglyceride synthesis. Mice lacking DGAT1 are resistant to obesity and have increased sensitivity to insulin and leptin. DGAT1-deficient mice are also resistant to diet-induced hepatic steatosis. The effects of DGAT1 deficiency on energy and glucose metab. result in part from the altered secretion of adipocyte-derived factors. Although complete DGAT1 deficiency causes alopecia and impairs development of the mammary gland, these abnormalities are not obsd. in mice with partial DGAT1 deficiency. These findings suggest that pharmacol. inhibition of DGAT1 may be a feasible therapeutic strategy for human obesity and type 2 diabetes.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhtl2ktLc%253D&md5=4fbd05dd60640345716cfe464a494e71

     
155. 155

     Cao, J.; Cheng, L.; Shi, Y. Catalytic Properties of MGAT3, a Putative Triacylgycerol Synthase. J. Lipid Res. 2007, 48, 583– 591,  DOI: 10.1194/jlr.M600331-JLR200

     [Crossref], [PubMed], [CAS], Google Scholar

     155

     Catalytic properties of MGAT3, a putative triacylgycerol synthase

     Cao, Jingsong; Cheng, Long; Shi, Yuguang

     Journal of Lipid Research (2007), 48 (3), 583-591CODEN: JLPRAW; ISSN:0022-2275. (American Society for Biochemistry and Molecular Biology, Inc.)

     Acyl-CoA:monoacylglycerol acyltransferase 3 (MGAT3) is a member of the MGAT family of enzymes that catalyze the synthesis of diacylglycerol (DAG) from monoacylglycerol (MAG), a committed step in dietary fat absorption. Although named after the initial identification of its MGAT activity, MGAT3 shares higher sequence homol. with acyl-CoA:diacylglycerol acyltransferase 2 (DGAT2) than with other MGAT enzymes, suggesting that MGAT3 may also possess significant DGAT activity. This study compared the catalytic properties of MGAT3 with those of MGAT1 and MGAT2 enzymes using both MAG and DAG as substrates. Our results showed that in addn. to the expected MGAT activity, the recombinant MGAT3 enzyme expressed in Sf-9 insect cells displayed a strong DGAT activity relative to that of MGAT1 and MGAT2 enzymes in the order MGAT3 > MGAT1 > MGAT2. In contrast, none of the three MGAT enzymes recognized biotinylated acyl-CoA or MAG as a substrate. Although MGAT3 possesses full DGAT activity, it differs from DGAT1 in catalytic properties and subcellular localization. The MGAT3 activity was sensitive to inhibition by the presence of 1% CHAPS, whereas DGAT1 activity was stimulated by the detergent. Consistent with high sequence homol. with DGAT2, the MGAT3 enzyme demonstrated a similar subcellular distribution pattern to that of DGAT2, but not DGAT1, when expressed in COS-7 cells. Our data suggest that MGAT3 functions as a novel triacylglycerol (TAG) synthase that catalyzes efficiently the two consecutive acylation steps in TAG synthesis.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXis1yqt7g%253D&md5=e90bcc3b7d69d746bb6133737fd16e52

     
156. 156

     Cheng, D.; Iqbal, J.; Devenny, J.; Chu, C. H.; Chen, L.; Dong, J.; Seethala, R.; Keim, W. J.; Azzara, A. V.; Lawrence, R. M.; Pelleymounter, M. A.; Hussain, M. M. Acylation of Acylglycerols by Acyl Coenzyme A:Diacylglycerol Acyltransferase 1 (DGAT1). Functional Importance of DGAT1 in the Intestinal Fat Absorption. J. Biol. Chem. 2008, 283, 29802– 29811,  DOI: 10.1074/jbc.M800494200

     [Crossref], [PubMed], [CAS], Google Scholar

     156

     Acylation of Acylglycerols by Acyl Coenzyme A:Diacylglycerol Acyltransferase 1 (DGAT1): functional importance of DGAT1 in the intestinal fat absorption

     Cheng, Dong; Iqbal, Jahangir; Devenny, James; Chu, Ching-Hsuen; Chen, Luping; Dong, Jessica; Seethala, Ramakrishna; Keim, William J.; Azzara, Anthony V.; Lawrence, R. Michael; Pelleymounter, Mary Ann; Hussain, M. Mahmood

     Journal of Biological Chemistry (2008), 283 (44), 29802-29811CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)

     Acyl CoA:diacylglycerol acyltransferase 1 (DGAT1) is one of the four intestinal membrane bound acyltransferases implicated in dietary fat absorption. Recently, it was found that, in addn. to acylating diacylglycerol (DAG), DGAT1 also possesses robust enzymic activity for acylating monoacylglycerol (MAG) (Yen, C. L., Monetti, M., Burri, B. J., and Farese, R. V., Jr. (2005) J. Lipid Res. 46, 1502-1511). In the current paper, we have conducted a detailed characterization of this reaction in test tube, intact cell culture, and animal models. Enzymically, we found that triacylglycerol (TAG) synthesis from MAG by DGAT1 does not behave according to classic Michaelis-Menten kinetics. At low concns. of 2-MAG (<50 μM), the major acylation product by DGAT1 was TAG; however, increased concns. of 2-MAG (50-200 μM) resulted in decreased TAG formation. This unique product/substrate relationship is similar to MGAT3 but distinct from DGAT2 and MGAT2. We have also found that XP620 is an inhibitor that selectively inhibits the acylation of MAG by DGAT1 (IC50 of human DGAT1: 16.6±4.0 nM (MAG as substrate) and 1499±318 nM (DAG as substrate); IC50 values of human DGAT2, MGAT2, and MGAT3 are >30,000 nM). Using this pharmacol. tool, we have shown that ∼76 and ∼89% of the in vitro TAG synthesis initiated from MAG is mediated by DGAT1 in Caco-2 cell and rat intestinal mucosal membranes, resp. When applied to intact cultured cells, XP620 substantially decreased but did not abolish apoB secretion in differentiated Caco-2 cells. It also decreased TAG and DAG syntheses in primary enterocytes. Last, when delivered orally to rats, XP620 decreased absorption of orally administered lipids by ∼50%. Based on these data, we conclude that the acylation of acylglycerols by DGAT1 is important for dietary fat absorption in the intestine.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXht1ynt7jI&md5=c1d97c53a3c6b202ff251167e45458e2

     
157. 157

     Smith, S. J.; Cases, S.; Jensen, D. R.; Chen, H. C.; Sande, E.; Tow, B.; Sanan, D. A.; Raber, J.; Eckel, R. H.; Farese, R. V., Jr. Obesity Resistance and Multiple Mechanisms of Triglyceride Synthesis in Mice Lacking Dgat. Nat. Genet. 2000, 25, 87– 90,  DOI: 10.1038/75651

     [Crossref], [PubMed], [CAS], Google Scholar

     157

     Obesity resistance and multiple mechanisms of triglyceride synthesis in mice lacking Dgat

     Smith, Steven J.; Cases, Sylvaine; Jensen, Dalan R.; Chen, Hubert C.; Sande, Eric; Tow, Bryan; Sanan, David A.; Raber, Jacob; Eckel, Robert H.; Farese, Robert V., Jr.

     Nature Genetics (2000), 25 (1), 87-90CODEN: NGENEC; ISSN:1061-4036. (Nature America Inc.)

     Triglycerides (or triacylglycerols) represent the major form of stored energy in eukaryotes. Triglyceride synthesis has been assumed to occur primarily through acyl CoA:diacylglycerol transferase (Dgat), a microsomal enzyme that catalyzes the final and only committed step in the glycerol phosphate pathway. Therefore, Dgat has been considered necessary for adipose tissue formation and essential for survival. Here the authors show that Dgat-deficient (Dgat-/-) mice are viable and can still synthesize triglycerides. Moreover, these mice are lean and resistant to diet-induced obesity. The obesity resistance involves increased energy expenditure and increased activity. Dgat deficiency also alters triglyceride metab. in other tissues, including the mammary gland, where lactation is defective in Dgat-/- females. The authors' findings indicate that multiple mechanisms exist for triglyceride synthesis and suggest that the selective inhibition of Dgat-mediated triglyceride synthesis may be useful for treating obesity.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXjtFSlt78%253D&md5=eeb60e9067f0d5ff9dbceb260ad0f61b

     
158. 158

     Stone, S. J.; Myers, H. M.; Watkins, S. M.; Brown, B. E.; Feingold, K. R.; Elias, P. M.; Farese, R. V., Jr. Lipopenia and Skin Barrier Abnormalities in DGAT2-Deficient Mice. J. Biol. Chem. 2004, 279, 11767– 11776,  DOI: 10.1074/jbc.M311000200

     [Crossref], [PubMed], [CAS], Google Scholar

     158

     Lipopenia and Skin Barrier Abnormalities in DGAT2-deficient Mice

     Stone, Scot J.; Myers, Heather M.; Watkins, Steven M.; Brown, Barbara E.; Feingold, Kenneth R.; Elias, Peter M.; Farese, Robert V., Jr.

     Journal of Biological Chemistry (2004), 279 (12), 11767-11776CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)

     The synthesis of triglycerides is catalyzed by two known acyl-CoA:diacylglycerol acyltransferase (DGAT) enzymes. Although they catalyze the same biochem. reaction, these enzymes share no sequence homol., and their relative functions are poorly understood. Gene knockout studies in mice have revealed that DGAT1 contributes to triglyceride synthesis in tissues and plays an important role in regulating energy metab. but is not essential for life. Here we show that DGAT2 plays a fundamental role in mammalian triglyceride synthesis and is required for survival. DGAT2-deficient (Dgat2-/-) mice are lipopenic and die soon after birth, apparently from profound redns. in substrates for energy metab. and from impaired permeability barrier function in the skin. DGAT1 was unable to compensate for the absence of DGAT2, supporting the hypothesis that the two enzymes play fundamentally different roles in mammalian triglyceride metab.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXitFyhu78%253D&md5=ff69c3357d21a37c8464192f605a54ba

     
159. 159

     Choi, C. S.; Savage, D. B.; Kulkarni, A.; Yu, X. X.; Liu, Z. X.; Morino, K.; Kim, S.; Distefano, A.; Samuel, V. T.; Neschen, S.; Zhang, D.; Wang, A.; Zhang, X. M.; Kahn, M.; Cline, G. W.; Pandey, S. K.; Geisler, J. G.; Bhanot, S.; Monia, B. P.; Shulman, G. I. Suppression of Diacylglycerol Acyltransferase-2 (DGAT2), but not DGAT1, with Antisense Oligonucleotides Reverses Diet-Induced Hepatic Steatosis and Insulin Resistance. J. Biol. Chem. 2007, 282, 22678– 22688,  DOI: 10.1074/jbc.M704213200

     [Crossref], [PubMed], [CAS], Google Scholar

     159

     Suppression of Diacylglycerol Acyltransferase-2 (DGAT2), but Not DGAT1, with Antisense Oligonucleotides Reverses Diet-induced Hepatic Steatosis and Insulin Resistance

     Choi, Cheol Soo; Savage, David B.; Kulkarni, Ameya; Yu, Xing Xian; Liu, Zhen-Xiang; Morino, Katsutaro; Kim, Sheene; Distefano, Alberto; Samuel, Varman T.; Neschen, Susanne; Zhang, Dongyan; Wang, Amy; Zhang, Xian-Man; Kahn, Mario; Cline, Gary W.; Pandey, Sanjay K.; Geisler, John G.; Bhanot, Sanjay; Monia, Brett P.; Shulman, Gerald I.

     Journal of Biological Chemistry (2007), 282 (31), 22678-22688CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)

     Nonalcoholic fatty liver disease (NAFLD) is a major contributing factor to hepatic insulin resistance in type 2 diabetes. Diacylglycerol acyltransferase (Dgat), of which there are two isoforms (Dgat1 and Dgat2), catalyzes the final step in triglyceride synthesis. The authors evaluated the metabolic impact of pharmacol. redn. of DGAT1 and -2 expression in liver and fat using antisense oligonucleotides (ASOs) in rats with diet-induced NAFLD. Dgat1 and Dgat2 ASO treatment selectively reduced DGAT1 and DGAT2 mRNA levels in liver and fat, but only Dgat2 ASO treatment significantly reduced hepatic lipids (diacylglycerol and triglyceride but not long chain acyl CoAs) and improved hepatic insulin sensitivity. Because Dgat catalyzes triglyceride synthesis from diacylglycerol, and because the authors have hypothesized that diacylglycerol accumulation triggers fat-induced hepatic insulin resistance through protein kinase Cε activation, the authors next sought to understand the paradoxical redn. in diacylglycerol in Dgat2 ASO-treated rats. Within 3 days of starting Dgat2 ASO therapy in high fat-fed rats, plasma fatty acids increased, whereas hepatic lysophosphatidic acid and diacylglycerol levels were similar to those of control rats. These changes were assocd. with reduced expression of lipogenic genes (SREBP1c, ACC1, SCD1, and mtGPAT) and increased expression of oxidative/thermogenic genes (CPT1 and UCP2). Taken together, these data suggest that knocking down Dgat2 protects against fat-induced hepatic insulin resistance by paradoxically lowering hepatic diacylglycerol content and protein kinase Cε activation through decreased SREBP1c-mediated lipogenesis and increased hepatic fatty acid oxidn.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXot1Wjurw%253D&md5=9f6f51990b7dbdaada58fa28af079a82

     
160. 160

     Naik, R.; Obiang-Obounou, B. W.; Kim, M.; Choi, Y.; Lee, H. S.; Lee, K. Therapeutic Strategies for Metabolic Diseases: Small-Molecule Diacylglycerol Acyltransferase (DGAT) Inhibitors. ChemMedChem 2014, 9, 2410– 2424,  DOI: 10.1002/cmdc.201402069

     [Crossref], [PubMed], [CAS], Google Scholar

     160

     Therapeutic Strategies for Metabolic Diseases: Small-Molecule Diacylglycerol Acyltransferase (DGAT) Inhibitors

     Naik, Ravi; Obiang-Obounou, Brice W.; Kim, Minkyoung; Choi, Yongseok; Lee, Hyun Sun; Lee, Kyeong

     ChemMedChem (2014), 9 (11), 2410-2424CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)

     A review. Metabolic diseases such as atherogenic dyslipidemia, hepatic steatosis, obesity, and type II diabetes are emerging as major global health problems. Acyl-CoA:diacylglycerol acyltransferase (DGAT) is responsible for catalyzing the final reaction in the glycerol phosphate pathway of triglycerol synthesis. It has two isoforms, DGAT-1 and DGAT-2, which are widely expressed and present in white adipose tissue. DGAT-1 is most highly expressed in the small intestine, whereas DGAT-2 is primarily expressed in the liver. Therefore, the selective inhibition of DGAT-1 has become an attractive target with growing potential for the treatment of obesity and type II diabetes. Furthermore, DGAT-2 has been suggested as a new target for the treatment of DGAT-2-related liver diseases including hepatic steatosis, hepatic injury, and fibrosis. In view the discovery of drugs that target DGAT, herein the authors attempt to provide insight into the scope and further reasons for optimization of DGAT inhibitors.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtVWgt7bI&md5=5bf25ab47bc2d0da07c65fd186534a5e

     
161. 161

     DeVita, R. J.; Pinto, S. Current Status of the Research and Development of Diacylglycerol O-Acyltransferase 1 (DGAT1) Inhibitors. J. Med. Chem. 2013, 56, 9820– 9825,  DOI: 10.1021/jm4007033

     [ACS Full Text ], [CAS], Google Scholar

     161

     Current Status of the Research and Development of Diacylglycerol O-Acyltransferase 1 (DGAT1) Inhibitors

     DeVita, Robert J.; Pinto, Shirly

     Journal of Medicinal Chemistry (2013), 56 (24), 9820-9825CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

     A review. Diacylglycerol O-acyltransferase 1 (DGAT1) has recently become a highly interesting target for metabolic disorders as well as for hepatitis C virus (HCV). DGAT1 processes diacylglycerol to triglycerides in the final step of resynthesis for the absorption of fat across the intestine. Pharmaceutical companies have developed many novel inhibitors of DGAT1, several of which have reached the clinic. Proof of target engagement was achieved with the observation of reduced triglycerides upon treatment of humans with DGAT1 inhibitors; however, there were gastrointestinal adverse events such as nausea, diarrhea, and vomiting. These adverse events have been reported with multiple compds. and are possibly linked to the target because of the recent identification of a human cohort deficient in DGAT1. Clin. studies are continuing in a trial to treat patients with an orphan indication for familial chylomicronemia. The full potential of DGAT1 as a therapeutic target will need to overcome obsd. clin. adverse events, which are possibly mechanism based. The widespread use of DGAT1 inhibitors will ultimately depend upon a better understanding of how to improve the GI tolerability of these agents.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXht1amtrjF&md5=821a9eed5072939780173e8ac2542d26

     
162. 162

     Barlind, J. G.; Bauer, U. A.; Birch, A. M.; Birtles, S.; Buckett, L. K.; Butlin, R. J.; Davies, R. D.; Eriksson, J. W.; Hammond, C. D.; Hovland, R.; Johannesson, P.; Johansson, M. J.; Kemmitt, P. D.; Lindmark, B. T.; Morentin Gutierrez, P.; Noeske, T. A.; Nordin, A.; O’Donnell, C. J.; Petersson, A. U.; Redzic, A.; Turnbull, A. V.; Vinblad, J. Design and Optimization of Pyrazinecarboxamide-Based Inhibitors of Diacylglycerol Acyltransferase 1 (DGAT1) Leading to a Clinical Candidate Dimethylpyrazinecarboxamide Phenylcyclohexylacetic Acid (AZD7687). J. Med. Chem. 2012, 55, 10610– 10629,  DOI: 10.1021/jm301296t

     [ACS Full Text ], [CAS], Google Scholar

     162

     Design and Optimization of Pyrazinecarboxamide-Based Inhibitors of Diacylglycerol Acyltransferase 1 (DGAT1) Leading to a Clinical Candidate Dimethylpyrazinecarboxamide Phenylcyclohexylacetic Acid (AZD7687)

     Barlind, Jonas G.; Bauer, Udo A.; Birch, Alan M.; Birtles, Susan; Buckett, Linda K.; Butlin, Roger J.; Davies, Robert D. M.; Eriksson, Jan W.; Hammond, Clare D.; Hovland, Ragnar; Johannesson, Petra; Johansson, Magnus J.; Kemmitt, Paul D.; Lindmark, Bo T.; Morentin Gutierrez, Pablo; Noeske, Tobias A.; Nordin, Andreas; O'Donnell, Charles J.; Petersson, Annika U.; Redzic, Alma; Turnbull, Andrew V.; Vinblad, Johanna

     Journal of Medicinal Chemistry (2012), 55 (23), 10610-10629CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

     A new series of pyrazinecarboxamide DGAT1 inhibitors was designed to address the need for a candidate drug with good potency, selectivity, and phys. and DMPK properties combined with a low predicted dose in man. Rational design and optimization of this series led to the discovery of compd. 30 (AZD7687), which met the project objectives for potency, selectivity, in particular over ACAT1, soly., and preclin. PK profiles. This compd. showed the anticipated excellent pharmacokinetic properties in human volunteers.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xhs1WgsbnF&md5=649d1b46b4df2d18e7811924dc17fcb9

     
163. 163

     Denison, H.; Nilsson, C.; Kujacic, M.; Lofgren, L.; Karlsson, C.; Knutsson, M.; Eriksson, J. W. Proof of Mechanism for the DGAT1 Inhibitor AZD7687: Results From a First-Time-In-Human Single-Dose Study. Diabetes, Obes. Metab. 2013, 15, 136– 143,  DOI: 10.1111/dom.12002

     [Crossref], [PubMed], [CAS], Google Scholar

     163

     Proof of mechanism for the DGAT1 inhibitor AZD7687: results from a first-time-in-human single-dose study

     Denison, H.; Nilsson, C.; Kujacic, M.; Loefgren, L.; Karlsson, C.; Knutsson, M.; Eriksson, J. W.

     Diabetes, Obesity and Metabolism (2013), 15 (2), 136-143CODEN: DOMEF6; ISSN:1462-8902. (Wiley-Blackwell)

     Aims : Inhibition of diacylglycerol acyltransferase 1 (DGAT1), which catalyzes the final step in triacylglycerol (TAG) assembly, is suggested as a treatment for type 2 diabetes and obesity based on animal data indicating insulin sensitization and wt. redn. This first-time-in-human single ascending dose study explored the safety, tolerability, pharmacokinetics and pharmacodynamics of the selective DGAT1 inhibitor AZD7687. Methods : Eighty healthy male subjects were enrolled. In each of 10 cohorts, six subjects received the same dose of AZD7687 orally (range across cohorts 1-60 mg) and two placebo. Plasma AZD7687 exposure was measured repeatedly. Postprandial serum TAG excursion was measured during 8 h after a standardized mixed meal with fat energy content of 60% (SMM 60%; five cohorts, 1-20 mg), before (baseline) and after dosing, to assess effects on gut DGAT1 activity. Results : AZD7687 markedly reduced postprandial TAG excursion with a steep concn.-effect relationship. Incremental TAG AUC (area under the serum concn. vs. time curve) following SMM 60% was decreased >75% from baseline at doses ≥5 mg (p < 0.0001 vs. placebo). Serum levels of diacylglycerol, specifically measured with mass spectrometry, did not increase after AZD7687 administration. Nausea, vomiting and diarrhea were reported with increasing doses and they limited dose escalation. Lowering of SMM fat content to 45 or 30% in five cohorts gradually reduced the frequency of gastrointestinal symptoms at a given dose of AZD7687. Conclusions : The attenuating effect of AZD7687 on postprandial TAG excursion provides proof of mechanism with respect to gut DGAT1 inhibition. However, dose and diet-related gastrointestinal side effects may impact further development of DGAT1 inhibitors.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXjs1SqtQ%253D%253D&md5=f7610927539d8da6c437559667e444ea

     
164. 164

     Escribano, A. M.; Gonzalez, M. R.; Blanco, C. L.; Finger, M. D. M.-O.; Wiley, M. R. Novel DGAT2 Inhibitors. International Patent WO2016187384, 2016.

     Google Scholar

     There is no corresponding record for this reference.

     
165. 165

     Camp, P. N.; Naik, M. Novel DGAT2 Inhibitors. International Patent WO2015077299, 2015.

     Google Scholar

     There is no corresponding record for this reference.

     
166. 166

     Boehm, M.; Cabral, S.; Dowling, M. S.; Futatsugi, K.; Huard, K. Diacylglycerol Acyltransferase 2 Inhibitors. International Patent WO2018033832, 2018.

     Google Scholar

     There is no corresponding record for this reference.

     
167. 167

     O’Gorman, P.; Naimimohasses, S.; Monaghan, A.; Kennedy, M.; Finn, S.; Gormley, J.; Norris, S. An International, Randomized, Placebo-Controlled Phase 2 Trial Demonstrates Novel Effects of DGAT2 Antisense Inhibition in Reducing Steatosis without causing Hypertriglyceridemia in T2DM Patients. Presented at the European Associate for the Study of the Liver International Liver Conference, Vienna, Austria, April 10–14, 2019; PS-106.

     Google Scholar

     There is no corresponding record for this reference.

     
168. 168

     Liu, H.; Liu, J. Y.; Wu, X.; Zhang, J. T. Biochemistry, Molecular Biology, and Pharmacology of Fatty Acid Synthase, An Emerging Therapeutic Target and Diagnosis/Prognosis Marker. Int. J. Biochem. Mol. Biol. 2010, 1, 69– 89

     [PubMed], [CAS], Google Scholar

     168

     Biochemistry, molecular biology, and pharmacology of fatty acid synthase, an emerging therapeutic target and diagnosis/prognosis marker

     Liu, Hailan; Liu, Jing-Yuan; Wu, Xi; Zhang, Jian-Ting

     International Journal of Biochemistry and Molecular Biology (2010), 1 (1), 69-89CODEN: IJBMHV; ISSN:2152-4114. (e-Century Publishing Corp.)

     A review. Human fatty acid synthase (FASN) is a 270-kDa cytosolic dimeric enzyme that is responsible for palmitate synthesis. FASN is slowly emerging and rediscovered as a marker for diagnosis and prognosis of human cancers. Recent studies showed that FASN is an oncogene and inhibition of FASN effectively and selectively kill cancer cells. With recent publications of the FASN crystal structure and the new development of FASN inhibitors, targeting FASN opens a new window of opportunity for metabolically combating cancers. In this article, we will review critically the recent progresses in understanding the structure, function, and the role of FASN in cancers and pharmacol. targeting FASN for human cancer treatment.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXitlOrurg%253D&md5=627e01eb9e0748f992d87cb14b410670

     
169. 169

     Abramson, H. N. The Lipogenesis Pathway as a Cancer Target. J. Med. Chem. 2011, 54, 5615– 5638,  DOI: 10.1021/jm2005805

     [ACS Full Text ], [CAS], Google Scholar

     169

     The Lipogenesis Pathway as a Cancer Target

     Abramson, Hanley N.

     Journal of Medicinal Chemistry (2011), 54 (16), 5615-5638CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

     A review. The role in lipogenesis metabolic pathway as cancer therapy target is discussed in this review.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXpslGitLo%253D&md5=e18bb3080a5747acf8f9eda49f536d18

     
170. 170

     Jones, S. F.; Infante, J. R. Molecular Pathways: Fatty Acid Synthase. Clin. Cancer Res. 2015, 21, 5434– 5438,  DOI: 10.1158/1078-0432.CCR-15-0126

     [Crossref], [PubMed], [CAS], Google Scholar

     170

     Molecular Pathways: Fatty Acid Synthase

     Jones, Suzanne F.; Infante, Jeffrey R.

     Clinical Cancer Research (2015), 21 (24), 5434-5438CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)

     Therapies that target tumor metab. represent a new horizon in anticancer therapies. In particular, cancer cells are dependent on the generation of lipids, which are essential for cell membrane synthesis, modification of proteins, and localization of many oncogenic signal transduction enzymes. Because fatty acids are the building blocks of these important lipids, fatty acid synthase (FASN) emerges as a unique oncol. target. FASN inhibitors are being studied preclinically and beginning to transition to first-in-human trials. Early generation FASN inhibitors have been studied preclinically but were limited by their pharmacol. properties and side-effect profiles. A new generation of mols., including GSK2194069, JNJ-54302833, IPI-9119, and TVB-2640, are in development, but only TVB-2640 has moved into the clinic. FASN inhibition, either alone or in combination, holds promise as a novel therapeutic approach for patients with cancer. Clin Cancer Res; 21(24); 5434-8. ©2015 AACR.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXitVKjs7vI&md5=a85caec09abc518b2c54a57612ebf382

     
171. 171

     Angeles, T. S.; Hudkins, R. L. Recent Advances in Targeting the Fatty Acid Biosynthetic Pathway Using Fatty Acid Synthase Inhibitors. Expert Opin. Drug Discovery 2016, 11, 1187– 1199,  DOI: 10.1080/17460441.2016.1245286

     [Crossref], [PubMed], [CAS], Google Scholar

     171

     Recent advances in targeting the fatty acid biosynthetic pathway using fatty acid synthase inhibitors

     Angeles, Thelma S.; Hudkins, Robert L.

     Expert Opinion on Drug Discovery (2016), 11 (12), 1187-1199CODEN: EODDBX; ISSN:1746-0441. (Taylor & Francis Ltd.)

     Elevated lipogenesis has been assocd. with a variety of diseases including obesity, cancer and nonalcoholic fatty liver disease (NAFLD). Fatty acid synthase (FASN) plays a pivotal role in de novo lipogenesis, making this multi-catalytic protein an attractive target for therapeutic intervention. Recently, the first FASN inhibitor successfully advanced through the drug development process and entered clin. evaluation in oncol. This review discusses the biol. roles of FASN in three prominent disease areas: cancer, obesity-related disorders and NAFLD. Recent advances in drug discovery strategies and design of newer FASN inhibitors are also highlighted. Despite the abundance of evidence linking the lipogenic pathway to cancer, progression of FASN-targeted mols. has been rather slow and challenging and no compds. have moved past the preclin. phase. The landscape has recently changed with the recent advancement of the first FASN inhibitor into clin. evaluation for solid tumors. Needless to say, the successful translation into the clin. setting will open opportunities for expanding the therapeutic utility of FASN inhibitors not just in oncol. but in other diseases assocd. with elevated lipogenesis such as obesity, type 2 diabetes, and NAFLD.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhslSqsLvO&md5=12c96f75d14e91746fd9968804ea111a

     
172. 172

     Turrado, C.; Puig, T.; Garcia-Carceles, J.; Artola, M.; Benhamu, B.; Ortega-Gutierrez, S.; Relat, J.; Oliveras, G.; Blancafort, A.; Haro, D.; Marrero, P. F.; Colomer, R.; Lopez-Rodriguez, M. L. New Synthetic Inhibitors of Fatty Acid Synthase with Anticancer Activity. J. Med. Chem. 2012, 55, 5013– 5023,  DOI: 10.1021/jm2016045

     [ACS Full Text ], [CAS], Google Scholar

     172

     New Synthetic Inhibitors of Fatty Acid Synthase with Anticancer Activity

     Turrado, Carlos; Puig, Teresa; Garcia-Carceles, Javier; Artola, Marta; Benhamu, Bellinda; Ortega-Gutierrez, Silvia; Relat, Joana; Oliveras, Gloria; Blancafort, Adriana; Haro, Diego; Marrero, Pedro F.; Colomer, Ramon; Lopez-Rodriguez, Maria L.

     Journal of Medicinal Chemistry (2012), 55 (11), 5013-5023CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

     Fatty acid synthase (FASN) is a lipogenic enzyme that is highly expressed in different human cancers. Here we report the development of a new series of polyphenolic compds. 5-30 that have been evaluated for their cytotoxic capacity in SK-Br3 cells, a human breast cancer cell line with high FASN expression. The compds. with an IC50 < 50 μM have been tested for their ability to inhibit FASN activity. Among them, deriv. 30 (I) blocks the 90% of FASN activity at low concn. (4 μM), is highly cytotoxic in a broad panel of tumor cells, induces apoptosis, and blocks the activation of HER2, AKT, and ERK pathways. Remarkably, 30 does not activate carnitine palmitoyltransferase-1 (CPT-1) nor induces in mice wt. loss, which are the main drawbacks of other previously described FASN inhibitors. Thus, FASN inhibitor 30 may aid the validation of this enzyme as a therapeutic target for the treatment of cancer.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XmsFygsb8%253D&md5=83a7be3e2f53c33e37aa12808f2f283d

     
173. 173

     Jensen-Urstad, A. P.; Semenkovich, C. F. Fatty Acid Synthase and Liver Triglyceride Metabolism: Housekeeper or Messenger?. Biochim. Biophys. Acta, Mol. Cell Biol. Lipids 2012, 1821, 747– 753,  DOI: 10.1016/j.bbalip.2011.09.017

     [Crossref], [PubMed], [CAS], Google Scholar

     173

     Fatty acid synthase and liver triglyceride metabolism: Housekeeper or messenger?

     Jensen-Urstad, Anne P. L.; Semenkovich, Clay F.

     Biochimica et Biophysica Acta, Molecular and Cell Biology of Lipids (2012), 1821 (5), 747-753CODEN: BBMLFG; ISSN:1388-1981. (Elsevier B. V.)

     A review. Fatty acid synthase (FAS) catalyzes the de novo synthesis of fatty acids. In the liver, FAS has long been categorized as a housekeeping protein, producing fat for storage of energy when nutrients are present in excess. Most previous studies of FAS regulation have focused on the control of gene expression. However, recent findings suggest that hepatic FAS may also be involved in signaling processes that include activation of peroxisome proliferator-activated receptor α (PPARα). Moreover, reports of rapid alterations in FAS activity as well as findings of post-translational modifications of the FAS protein support the notion that dynamic events in addn. to transcription impact FAS regulation. These results indicate that FAS enzyme activity can impact liver physiol. through signaling as well as energy storage and that its regulation may be complex. This article is part of a Special Issue entitled Triglyceride Metab. and Disease.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xkslaktbo%253D&md5=27dd2e07465f7a1b08bd84cb71d2db71

     
174. 174

     Dorn, C.; Riener, M. O.; Kirovski, G.; Saugspier, M.; Steib, K.; Weiss, T. S.; Gabele, E.; Kristiansen, G.; Hartmann, A.; Hellerbrand, C. Expression of Fatty Acid Synthase in Nonalcoholic Fatty Liver Disease. Int. J. Clin. Exp. Pathol. 2010, 3, 505– 514

     [PubMed], [CAS], Google Scholar

     174

     Expression of fatty acid synthase in nonalcoholic fatty liver disease

     Dorn, Christoph; Riener, Marc-Oliver; Kirovski, Georgi; Saugspier, Michael; Steib, Kathrin; Weiss, Thomas S.; Gaebele, Erwin; Kristiansen, Glen; Hartmann, Arndt; Hellerbrand, Claus

     International Journal of Clinical and Experimental Pathology (2010), 3 (5), 505-514CODEN: IJCEC7; ISSN:1936-2625. (e-Century Publishing Corp.)

     Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic lipid accumulation which starts with simple hepatic steatosis and may progress toward inflammation (nonalcoholic steatohepatitis [NASH]). Fatty acid synthase (FASN) catalyzes the last step in fatty acid biosynthesis, and thus, it is believed to be a major determinant of the maximal hepatic capacity to generate fatty acids by de novo lipogenesis. The aim of this study was to analyze the correlation between hepatic steatosis and inflammation with FASN expression. In vitro incubation of primary human hepatocytes with fatty acids dose-dependently induced cellular lipid-accumulation and FASN expression, while stimulation with TNF did not affect FASN levels. Further, hepatic FASN expression was significantly increased in vivo in a murine model of hepatic steatosis without significant inflammation but not in a murine NASH model as compared to control mice. Also, FASN expression was not increased in mice subjected to bile duct ligation, an exptl. model characterized by severe hepatocellular damage and inflammation. Furthermore, FASN expression was analyzed in 102 human control or NAFLD livers applying tissue micro array technol. and immunohistochem., and correlated significantly with the degree of hepatic steatosis, but not with inflammation or ballooning of hepatocytes. Quantification of FASN mRNA expression in human liver samples confirmed significantly higher FASN levels in hepatic steatosis but not in NASH, and expression of SREBP1, which is the main transcriptional regulator of FASN, paralleled FASN expression levels in human and exptl. NAFLD. In conclusion, the transcriptional induction of FASN expression in hepatic steatosis is impaired in NASH, while hepatic inflammation in the absence of steatosis does not affect FASN expression, suggesting that FASN may serve as a new diagnostic marker or therapeutic target for the progression of NAFLD.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXotVyrtLs%253D&md5=79f785334dc36eabd116f88fbabd5f4f

     
175. 175

     Patel, M.; Infante, J.; Hoff, D. V.; Jones, S.; Burris, H.; Brenner, A.; McCulloch, W.; Zhukova-Harrill, V.; Kemble, G.; Parsey, M. Report of a First-In-Human Study of the First-In-Class Fatty Acid Synthase (FASN) Inhibitor TVB-2640. Presented at the 106th Annual Meeting of the American Association for Cancer Research, Philadelphia, USA, April 18–22, 2015; CT203.

     Google Scholar

     There is no corresponding record for this reference.

     
176. 176

     Forma Therapeutics. https://www.formatherapeutics.com/pipeline/ft-4101-ft-8225/ (accessed Sept 25, 2019).

     Google Scholar

     There is no corresponding record for this reference.

     
177. 177

     Beysen, C.; Dole, K.; Schroeder, P.; Brevard, J.; Ribadeneira, M.; Sheth, P.; Mishkin, A.; O’Reilly, T. E. Inhibition of Fatty Acid Synthase (FASN) with FT-4101 Reduces Hepatic De Novo Lipogenesis (DNL) in Healthy Adult Subjects. Presented at the American Association for the Study of Liver Diseases, Boston, USA, November 13–17, 2019; 2151.

     Google Scholar

     There is no corresponding record for this reference.

     
178. 178

     Bricker, D. K.; Taylor, E. B.; Schell, J. C.; Orsak, T.; Boutron, A.; Chen, Y. C.; Cox, J. E.; Cardon, C. M.; Van Vranken, J. G.; Dephoure, N.; Redin, C.; Boudina, S.; Gygi, S. P.; Brivet, M.; Thummel, C. S.; Rutter, J. A Mitochondrial Pyruvate Carrier Required for Pyruvate Uptake in Yeast, Drosophila, and Humans. Science 2012, 337, 96– 100,  DOI: 10.1126/science.1218099

     [Crossref], [PubMed], [CAS], Google Scholar

     178

     A Mitochondrial Pyruvate Carrier Required for Pyruvate Uptake in Yeast, Drosophila, and Humans

     Bricker, Daniel K.; Taylor, Eric B.; Schell, John C.; Orsak, Thomas; Boutron, Audrey; Chen, Yu-Chan; Cox, James E.; Cardon, Caleb M.; Van Vranken, Jonathan G.; Dephoure, Noah; Redin, Claire; Boudina, Sihem; Gygi, Steven P.; Brivet, Michele; Thummel, Carl S.; Rutter, Jared

     Science (Washington, DC, United States) (2012), 337 (6090), 96-100CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)

     Pyruvate constitutes a crit. branch point in cellular carbon metab. We have identified two proteins, Mpc1 and Mpc2, as essential for mitochondrial pyruvate transport in yeast, Drosophila, and humans. Mpc1 and Mpc2 assoc. to form an ~150-kilodalton complex in the inner mitochondrial membrane. Yeast and Drosophila mutants lacking MPC1 display impaired pyruvate metab., with an accumulation of upstream metabolites and a depletion of tricarboxylic acid cycle intermediates. Loss of yeast Mpc1 results in defective mitochondrial pyruvate uptake, and silencing of MPC1 or MPC2 in mammalian cells impairs pyruvate oxidn. A point mutation in MPC1 provides resistance to a known inhibitor of the mitochondrial pyruvate carrier. Human genetic studies of three families with children suffering from lactic acidosis and hyperpyruvatemia revealed a causal locus that mapped to MPC1, changing single amino acids that are conserved throughout eukaryotes. These data demonstrate that Mpc1 and Mpc2 form an essential part of the mitochondrial pyruvate carrier.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XpsFKksrw%253D&md5=249830b1bb03a2ba92b5d242c0aba25e

     
179. 179

     Herzig, S.; Raemy, E.; Montessuit, S.; Veuthey, J. L.; Zamboni, N.; Westermann, B.; Kunji, E. R.; Martinou, J. C. Identification and Functional Expression of the Mitochondrial Pyruvate Carrier. Science 2012, 337, 93– 96,  DOI: 10.1126/science.1218530

     [Crossref], [PubMed], [CAS], Google Scholar

     179

     Identification and Functional Expression of the Mitochondrial Pyruvate Carrier

     Herzig, Sebastien; Raemy, Etienne; Montessuit, Sylvie; Veuthey, Jean-Luc; Zamboni, Nicola; Westermann, Benedikt; Kunji, Edmund R. S.; Martinou, Jean-Claude

     Science (Washington, DC, United States) (2012), 337 (6090), 93-96CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)

     The transport of pyruvate, the end product of glycolysis, into mitochondria is an essential process that provides the organelle with a major oxidative fuel. Although the existence of a specific mitochondrial pyruvate carrier (MPC) has been anticipated, its mol. identity has remained unknown. We report here that MPC is a heterocomplex formed by two members of a family of previously uncharacterized membrane proteins that are conserved from yeast to mammals. Members of the MPC family were found in the inner mitochondrial membrane, and yeast mutants lacking MPC proteins showed severe defects in mitochondrial pyruvate uptake. Coexpression of mouse MPC1 and MPC2 in Lactococcus lactis promoted transport of pyruvate across the membrane. These observations firmly establish these proteins as essential components of the MPC.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XpsFKksr4%253D&md5=e586727ecbcc91e39f8d0dd2a4671648

     
180. 180

     Bender, T.; Martinou, J. C. The Mitochondrial Pyruvate Carrier in Health and Disease: To Carry or Not to Carry?. Biochim. Biophys. Acta, Mol. Cell Res. 2016, 1863, 2436– 2442,  DOI: 10.1016/j.bbamcr.2016.01.017

     [Crossref], [CAS], Google Scholar

     180

     The mitochondrial pyruvate carrier in health and disease: To carry or not to carry?

     Bender, Tom; Martinou, Jean-Claude

     Biochimica et Biophysica Acta, Molecular Cell Research (2016), 1863 (10), 2436-2442CODEN: BBAMCO; ISSN:0167-4889. (Elsevier B.V.)

     Mitochondria play a key role in energy metab., hosting the machinery for oxidative phosphorylation, the most efficient cellular pathway for generating ATP. A major checkpoint in this process is the transport of pyruvate produced by cytosolic glycolysis into the mitochondrial matrix, which is accomplished by the recently identified mitochondrial pyruvate carrier (MPC). As the gatekeeper for pyruvate entry into mitochondria, the MPC is thought to be of fundamental importance in establishing the metabolic programming of a cell. This is esp. relevant in the context of the aerobic glycolysis, also known as the Warburg effect, which is a hallmark in many types of cancer, and MPC loss of function promotes cancer growth. Moreover, mitochondrial pyruvate uptake is needed for efficient hepatic gluconeogenesis and the regulation of blood glucose levels. In this review we discuss recent advances in our knowledge of the MPC, and we argue that it may offer a promising target in diseases like cancer and type 2 diabetes.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xhs12hu78%253D&md5=6b9b5ca3cc3d1050ccd454e2ec221e19

     
181. 181

     Colca, J. R.; McDonald, W. G.; Kletzien, R. F. Mitochondrial Target of Thiazolidinediones. Diabetes, Obes. Metab. 2014, 16, 1048– 1054,  DOI: 10.1111/dom.12308

     [Crossref], [PubMed], [CAS], Google Scholar

     181

     Mitochondrial target of thiazolidinediones

     Colca, J. R.; McDonald, W. G.; Kletzien, R. F.

     Diabetes, Obesity and Metabolism (2014), 16 (11), 1048-1054CODEN: DOMEF6; ISSN:1462-8902. (Wiley-Blackwell)

     A review. Insulin-sensitizing thiazolidinediones exert a pleiotropic pharmacol. with therapeutic potential in a no. of disease states ranging from metabolic syndrome and diabetes to neurodegeneration and cancer. A growing understanding of their mechanism of action, working from the site of their binding in the mitochondrion, provides insight into the mechanism of action of the insulin sensitizers and the reasons for their pleiotropic pharmacol. This review helps to frame the direction of future work that should be helpful in setting a new direction for the discovery and development of new, more useful therapeutic agents for metabolic disease.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhslemtrfM&md5=e69343b77bd36339ac96201979d72d09

     
182. 182

     Colca, J. R.; Tanis, S. P.; McDonald, W. G.; Kletzien, R. F. Insulin Sensitizers in 2013: New Insights for the Development of Novel Therapeutic Agents to Treat Metabolic Diseases. Expert Opin. Invest. Drugs 2014, 23, 1– 7,  DOI: 10.1517/13543784.2013.839659

     [Crossref], [PubMed], [CAS], Google Scholar

     182

     Insulin sensitizers in 2013: new insights for the development of novel therapeutic agents to treat metabolic diseases

     Colca, Jerry R.; Tanis, Steven P.; McDonald, William G.; Kletzien, Rolf F.

     Expert Opinion on Investigational Drugs (2014), 23 (1), 1-7CODEN: EOIDER; ISSN:1354-3784. (Informa Healthcare)

     A review. Insulin-sensitizing thiazolidinediones (TZDs) correct a root cause of type 2 diabetes and potentially other diseases of metabolic dysfunction, including conditions ranging from oncol., inflammatory, and neurodegenerative diseases. Importantly, compds. with this mode of action can modify disease progression, as opposed to simply mitigating symptoms. However, side effects have limited the use of marketed agents. Moreover, the same and addnl. issues have prevented development of newer agents, and no new compds. with this mode of action have been approved since 1999. Here we briefly review the drug discovery track record of compds. in the TZD class as well as several classes of compds. that have been designed with substitutes for the TZD ring, while maintaining and/or expanding the ability to directly activate peroxisome proliferator-activated receptor (PPAR) transcription factors. A key discovery that could change the course of drug discovery in this area is a newly identified mitochondrial target for the insulin sensitizers. This has allowed new drug discovery into mols. designed to maintain this mitochondrial interaction while specifically avoiding significant interactions with PPAR receptors. This commentary suggests that a fresh approach could pave the way for a new directed group of therapeutic agents with potential for disease modification of common metabolic disorders.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvVyqsLnK&md5=35a1222ee37ed6cd5532c208b723befe

     
183. 183

     Colca, J. R.; McDonald, W. G.; Cavey, G. S.; Cole, S. L.; Holewa, D. D.; Brightwell-Conrad, A. S.; Wolfe, C. L.; Wheeler, J. S.; Coulter, K. R.; Kilkuskie, P. M.; Gracheva, E.; Korshunova, Y.; Trusgnich, M.; Karr, R.; Wiley, S. E.; Divakaruni, A. S.; Murphy, A. N.; Vigueira, P. A.; Finck, B. N.; Kletzien, R. F. Identification of a Mitochondrial Target of Thiazolidinedione Insulin Sensitizers (mTOT)–Relationship to Newly Identified Mitochondrial Pyruvate Carrier Proteins. PLoS One 2013, 8, e61551  DOI: 10.1371/journal.pone.0061551

     [Crossref], [PubMed], [CAS], Google Scholar

     183

     Identification of a mitochondrial target of thiazolidinedione insulin sensitizers (mTOT) - relationship to newly identified mitochondrial pyruvate carrier proteins

     Colca, Jerry R.; McDonald, William G.; Cavey, Gregory S.; Cole, Serena L.; Holewa, Danielle D.; Brightwell-Conrad, Angela S.; Wolfe, Cindy L.; Wheeler, Jean S.; Coulter, Kristin R.; Kilkuskie, Peter M.; Gracheva, Elena; Korshunova, Yulia; Trusgnich, Michelle; Karr, Robert; Wiley, Sandra E.; Divakaruni, Ajit S.; Murphy, Anne N.; Vigueira, Patrick A.; Finck, Brian N.; Kletzien, Rolf F.

     PLoS One (2013), 8 (5), e61551CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)

     Thiazolidinedione (TZD) insulin sensitizers have the potential to effectively treat a no. of human diseases, however the currently available agents have dose-limiting side effects that are mediated via activation of the transcription factor PPARγ. We have recently shown PPARγ-independent actions of TZD insulin sensitizers, but the mol. target of these mols. remained to be identified. Here we use a photo-catalyzable drug analog probe and mass spectrometry-based proteomics to identify a previously uncharacterized mitochondrial complex that specifically recognizes TZDs. These studies identify two well-conserved proteins previously known as brain protein 44 (BRP44) and BRP44 Like (BRP44L), which recently have been renamed Mpc2 and Mpc1 to signify their function as a mitochondrial pyruvate carrier complex. Knockdown of Mpc1 or Mpc2 in Drosophila melanogaster or pre-incubation with UK5099, an inhibitor of pyruvate transport, blocks the crosslinking of mitochondrial membranes by the TZD probe. Knockdown of these proteins in Drosophila also led to increased hemolymph glucose and blocked drug action. In isolated brown adipose tissue (BAT) cells, MSDC-0602, a PPARγ-sparing TZD, altered the incorporation of 13C-labeled carbon from glucose into acetyl CoA. These results identify Mpc1 and Mpc2 as components of the mitochondrial target of TZDs (mTOT) and suggest that understanding the modulation of this complex, which appears to regulate pyruvate entry into the mitochondria, may provide a viable target for insulin sensitizing pharmacol.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXosVKhsbw%253D&md5=ecc3245b69aa87e5d49312fe9741baef

     
184. 184

     Divakaruni, A. S.; Wiley, S. E.; Rogers, G. W.; Andreyev, A. Y.; Petrosyan, S.; Loviscach, M.; Wall, E. A.; Yadava, N.; Heuck, A. P.; Ferrick, D. A.; Henry, R. R.; McDonald, W. G.; Colca, J. R.; Simon, M. I.; Ciaraldi, T. P.; Murphy, A. N. Thiazolidinediones are Acute, Specific Inhibitors of the Mitochondrial Pyruvate Carrier. Proc. Natl. Acad. Sci. U. S. A. 2013, 110, 5422– 5427,  DOI: 10.1073/pnas.1303360110

     [Crossref], [PubMed], [CAS], Google Scholar

     184

     Thiazolidinediones are acute, specific inhibitors of the mitochondrial pyruvate carrier

     Divakaruni, Ajit S.; Wiley, Sandra E.; Rogers, George W.; Andreyev, Alexander Y.; Petrosyan, Susanna; Loviscach, Mattias; Wall, Estelle A.; Yadava, Nagendra; Heuck, Alejandro P.; Ferrick, David A.; Henry, Robert R.; McDonald, William G.; Colca, Jerry R.; Simon, Melvin I.; Ciaraldi, Theodore P.; Murphy, Anne N.

     Proceedings of the National Academy of Sciences of the United States of America (2013), 110 (14), 5422-5427, S5422/1-S5422/4CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)

     Facilitated pyruvate transport across the mitochondrial inner membrane is a crit. step in carbohydrate, amino acid, and lipid metab. We report that clin. relevant concns. of thiazolidinediones (TZDs), a widely used class of insulin sensitizers, acutely and specifically inhibit mitochondrial pyruvate carrier (MPC) activity in a variety of cell types. Respiratory inhibition was overcome with Me pyruvate, localizing the effect to facilitated pyruvate transport, and knockdown of either paralog, MPC1 or MPC2, decreased the EC5 for respiratory inhibition by TZDs. Acute MPC inhibition significantly enhanced glucose uptake in human skeletal muscle myocytes after 2 h. These data (i) report that clin. used TZDs inhibit the MPC, (ii) validate that MPC1 and MPC2 are obligatory components of facilitated pyruvate transport in mammalian cells, (iii) indicate that the acute effect of TZDs may be related to insulin sensitization, and (iv) establish mitochondrial pyruvate uptake as a potential therapeutic target for diseases rooted in metabolic dysfunction.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXntVehurg%253D&md5=13ef0104780cb3ce994b25d2644d2546

     
185. 185

     Divakaruni, A. S.; Murphy, A. N. Cell Biology. A Mitochondrial Mystery, Solved. Science 2012, 337, 41– 43,  DOI: 10.1126/science.1225601

     [Crossref], [PubMed], [CAS], Google Scholar

     185

     A mitochondrial mystery, solved

     Divakaruni, Ajit S.; Murphy, Anne N.

     Science (Washington, DC, United States) (2012), 337 (6090), 41-43CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)

     There is no expanded citation for this reference.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtVygurjO&md5=0d715b34f7750d1bb7c5ccac7e893582

     
186. 186

     Walheim, E.; Wisniewski, J. R.; Jastroch, M. Respiromics - An Integrative Analysis Linking Mitochondrial Bioenergetics to Molecular Signatures. Mol. Metab. 2018, 9, 4– 14,  DOI: 10.1016/j.molmet.2018.01.002

     [Crossref], [PubMed], [CAS], Google Scholar

     186

     Respiromics - An integrative analysis linking mitochondrial bioenergetics to molecular signatures

     Walheim, Ellen; Wisniewski, Jacek R.; Jastroch, Martin

     Molecular Metabolism (2018), 9 (), 4-14CODEN: MMOEAS; ISSN:2212-8778. (Elsevier GmbH)

     Energy metab. is challenged upon nutrient stress, eventually leading to a variety of metabolic diseases that represent a major global health burden.Here, we combine quant. mitochondrial respirometry (Seahorse technol.) and proteomics (LC-MS/MS-based total protein approach) to understand how mol. changes translate to changes in mitochondrial energy transduction during diet-induced obesity (DIO) in the liver.The integrative anal. reveals that significantly increased palmitoyl-carnitine respiration is supported by an array of proteins enriching lipid metab. pathways. Upstream of the respiratory chain, the increased capacity for ATP synthesis during DIO assocs. strongest to mitochondrial uptake of pyruvate, which is routed towards carboxylation. At the respiratory chain, robust increases of complex I are uncovered by cumulative anal. of single subunit concns. Specifically, nuclear-encoded accessory subunits, but not mitochondrial-encoded or core units, appear to be permissive for enhanced lipid oxidn.Our integrative anal., that we dubbed "respiromics", represents an effective tool to link mol. changes to functional mechanisms in liver energy metab., and, more generally, can be applied for mitochondrial anal. in a variety of metabolic and mitochondrial disease models.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXosl2qtQ%253D%253D&md5=172e05702a6d03f4a08cfa7f1a8e860e

     
187. 187

     Rauckhorst, A. J.; Gray, L. R.; Sheldon, R. D.; Fu, X.; Pewa, A. D.; Feddersen, C. R.; Dupuy, A. J.; Gibson-Corley, K. N.; Cox, J. E.; Burgess, S. C.; Taylor, E. B. The Mitochondrial Pyruvate Carrier Mediates High Fat Diet-Induced Increases in Hepatic TCA Cycle Capacity. Mol. Metab. 2017, 6, 1468– 1479,  DOI: 10.1016/j.molmet.2017.09.002

     [Crossref], [PubMed], [CAS], Google Scholar

     187

     The mitochondrial pyruvate carrier mediates high fat diet-induced increases in hepatic TCA cycle capacity

     Rauckhorst, Adam J.; Gray, Lawrence R.; Sheldon, Ryan D.; Fu, Xiaorong; Pewa, Alvin D.; Feddersen, Charlotte R.; Dupuy, Adam J.; Gibson-Corley, Katherine N.; Cox, James E.; Burgess, Shawn C.; Taylor, Eric B.

     Molecular Metabolism (2017), 6 (11), 1468-1479CODEN: MMOEAS; ISSN:2212-8778. (Elsevier GmbH)

     Excessive hepatic gluconeogenesis is a defining feature of type 2 diabetes (T2D). Most gluconeogenic flux is routed through mitochondria. The mitochondrial pyruvate carrier (MPC) transports pyruvate from the cytosol into the mitochondrial matrix, thereby gating pyruvate-driven gluconeogenesis. Disruption of the hepatocyte MPC attenuates hyperglycemia in mice during high fat diet (HFD)-induced obesity but exerts minimal effects on glycemia in normal chow diet (NCD)-fed conditions. The goal of this investigation was to test whether hepatocyte MPC disruption provides sustained protection from hyperglycemia during long-term HFD and the differential effects of hepatocyte MPC disruption on TCA cycle metab. in NCD vs. HFD conditions. We utilized long-term high fat feeding, serial measurements of postabsorptive blood glucose and metabolomic profiling and 13C-lactate/13C-pyruvate tracing to investigate the contribution of the MPC to hyperglycemia and altered hepatic TCA cycle metab. during HFD-induced obesity. Hepatocyte MPC disruption resulted in long-term attenuation of hyperglycemia induced by HFD. HFD increased hepatic mitochondrial pyruvate utilization and TCA cycle capacity in an MPC-dependent manner. Furthermore, MPC disruption decreased progression of fibrosis and levels of transcript markers of inflammation. By contributing to chronic hyperglycemia, fibrosis, and TCA cycle expansion, the hepatocyte MPC is a key mediator of the pathophysiol. induced in the HFD model of T2D.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsFeqtr%252FM&md5=e3a22b4c8d53f447f0b2fb7b84a45076

     
188. 188

     McCommis, K. S.; Hodges, W. T.; Brunt, E. M.; Nalbantoglu, I.; McDonald, W. G.; Holley, C.; Fujiwara, H.; Schaffer, J. E.; Colca, J. R.; Finck, B. N. Targeting the Mitochondrial Pyruvate Carrier Attenuates Fibrosis in a Mouse Model of Nonalcoholic Steatohepatitis. Hepatology 2017, 65, 1543– 1556,  DOI: 10.1002/hep.29025

     [Crossref], [PubMed], [CAS], Google Scholar

     188

     Targeting the mitochondrial pyruvate carrier attenuates fibrosis in a mouse model of nonalcoholic steatohepatitis

     McCommis, Kyle S.; Hodges, Wesley T.; Brunt, Elizabeth M.; Nalbantoglu, Ilke; McDonald, William G.; Holley, Christopher; Fujiwara, Hideji; Schaffer, Jean E.; Colca, Jerry R.; Finck, Brian N.

     Hepatology (Hoboken, NJ, United States) (2017), 65 (5), 1543-1556CODEN: HPTLD9; ISSN:0270-9139. (John Wiley & Sons, Inc.)

     Diseases of the liver related to metabolic syndrome have emerged as the most common and undertreated hepatic ailments. The cause of nonalcoholic fatty liver disease is the aberrant accumulation of lipid in hepatocytes, though the mechanisms whereby this leads to hepatocyte dysfunction, death, and hepatic fibrosis are still unclear. Insulin-sensitizing thiazolidinediones have shown efficacy in treating nonalcoholic steatohepatitis (NASH), but their widespread use is constrained by dose-limiting side effects thought to be due to activation of the peroxisome proliferator-activated receptor γ. We sought to det. whether a next-generation thiazolidinedione with markedly diminished ability to activate peroxisome proliferator-activated receptor γ (MSDC-0602) would retain its efficacy for treating NASH in a rodent model. We also detd. whether some or all of these beneficial effects would be mediated through an inhibitory interaction with the mitochondrial pyruvate carrier 2 (MPC2), which was recently identified as a mitochondrial binding site for thiazolidinediones, including MSDC-0602. We found that MSDC-0602 prevented and reversed liver fibrosis and suppressed expression of markers of stellate cell activation in livers of mice fed a diet rich in trans-fatty acids, fructose, and cholesterol. Moreover, mice with liver-specific deletion of MPC2 were protected from development of NASH on this diet. Finally, MSDC-0602 directly reduced hepatic stellate cell activation in vitro, and MSDC-0602 treatment or hepatocyte MPC2 deletion also limited stellate cell activation indirectly by affecting secretion of exosomes from hepatocytes. Conclusion: Collectively, these data demonstrate the effectiveness of MSDC-0602 for attenuating NASH in a rodent model and suggest that targeting hepatic MPC2 may be an effective strategy for pharmacol. development. (Hepatol. 2017;65:1543-1556).

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXmt12ltbY%253D&md5=51310dea06c58628db4f582b0d7fbb1d

     
189. 189

     Colca, J. R.; McDonald, W. G.; Adams, W. J. MSDC-0602K, a Metabolic Modulator Directed at the Core Pathology of Non-Alcoholic Steatohepatitis. Expert Opin. Invest. Drugs 2018, 27, 631– 636,  DOI: 10.1080/13543784.2018.1494153

     [Crossref], [PubMed], [CAS], Google Scholar

     189

     MSDC-0602K, a metabolic modulator directed at the core pathology of non-alcoholic steatohepatitis

     Colca, Jerry R.; McDonald, William G.; Adams, Wade J.

     Expert Opinion on Investigational Drugs (2018), 27 (7), 631-636CODEN: EOIDER; ISSN:1354-3784. (Taylor & Francis Ltd.)

     : Non-alc. steatohepatitis (NASH) is a serious form of non-alc. fatty liver disease (NAFLD) for which there is no marketed treatments. NAFLD is initiated by excess intake of nutrients and recent evidence has pinpointed the mitochondrial pyruvate carrier (MPC) as a mediator of the nutritional overload signals.: An overview is given of MSDC-0602K, a new agent in development that modulates the MPC and as such treats the symptoms of fatty liver including dysfunctional lipid metab., inflammation, and insulin resistance as well as the key liver pathol. including fibrosis.: The current evaluation is written from the direct experience of the authors and review of published literature using std. search techniques.: The mechanism of action of MSDC-0602K appears to be suited for treatment of the NASH pathophysiol. An ongoing phase 2b dose-ranging trial should demonstrate whether or not MSDC-0602K has the potential to be a cornerstone metabolic therapy for the treatment of NASH.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtlenurvE&md5=7b4bae3d040439e69df61a27682ca0ae

     
190. 190

     Chen, Z.; Vigueira, P. A.; Chambers, K. T.; Hall, A. M.; Mitra, M. S.; Qi, N.; McDonald, W. G.; Colca, J. R.; Kletzien, R. F.; Finck, B. N. Insulin Resistance and Metabolic Derangements in Obese Mice are Ameliorated by a Novel Peroxisome Proliferator-Activated Receptor Gamma-Sparing Thiazolidinedione. J. Biol. Chem. 2012, 287, 23537– 23548,  DOI: 10.1074/jbc.M112.363960

     [Crossref], [PubMed], [CAS], Google Scholar

     190

     Insulin Resistance and Metabolic Derangements in Obese Mice Are Ameliorated by a Novel Peroxisome Proliferator-activated Receptor γ-sparing Thiazolidinedione

     Chen, Zhouji; Vigueira, Patrick A.; Chambers, Kari T.; Hall, Angela M.; Mitra, Mayurranjan S.; Qi, Nathan; McDonald, William G.; Colca, Jerry R.; Kletzien, Rolf F.; Finck, Brian N.

     Journal of Biological Chemistry (2012), 287 (28), 23537-23548CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)

     Currently approved thiazolidinediones (TZDs) are effective insulin-sensitizing drugs that may have efficacy for treatment of a variety of metabolic and inflammatory diseases, but their use is limited by side effects that are mediated through ectopic activation of the peroxisome proliferator-activated receptor γ (PPARγ). Emerging evidence suggests that the potent anti-diabetic efficacy of TZDs can be sepd. from the ability to serve as ligands for PPARγ. A novel TZD analog (MSDC-0602) with very low affinity for binding and activation of PPARγ was evaluated for its effects on insulin resistance in obese mice. MSDC-0602 treatment markedly improved several measures of multiorgan insulin sensitivity, adipose tissue inflammation, and hepatic metabolic derangements, including suppressing hepatic lipogenesis and gluconeogenesis. These beneficial effects were mediated at least in part via direct actions on hepatocytes and were preserved in hepatocytes from liver-specific PPARγ-/- mice, indicating that PPARγ was not required to suppress these pathways. In conclusion, the beneficial pharmacol. exhibited by MSDC-0602 on insulin sensitivity suggests that PPARγ-sparing TZDs are effective for treatment of type 2 diabetes with reduced risk of PPARγ-mediated side effects.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XpvVejt7k%253D&md5=e32199e280818a09d3bb915a289afb85

     
191. 191

     Harrison, S. A.; Neff, G.; Davison, B.; Moussa, S.; Alkhouri, N.; Cusi, K.; Colca, J.; Sanyal, A. J.; Loomba, R.; Cotter, G.; Dittrich, H. Results of MSDC-0602K in a Large Phase 2b NASH Study Demonstrate Improvement in Markers of Insulin Resistance, Glucose Metabolism, Serum Aminotransferases, Non Invasive Markers of NASH and Histopathology. Presented at the American Association for the Study of Liver Diseases, Boston, USA, November 13–17, 2019; LO1.

     Google Scholar

     There is no corresponding record for this reference.

     
192. 192

     Molinaro, A.; Wahlstrom, A.; Marschall, H. U. Role of Bile Acids in Metabolic Control. Trends Endocrinol. Metab. 2018, 29, 31– 41,  DOI: 10.1016/j.tem.2017.11.002

     [Crossref], [PubMed], [CAS], Google Scholar

     192

     Role of Bile Acids in Metabolic Control

     Molinaro, Antonio; Wahlstroem, Annika; Marschall, Hanns-Ulrich

     Trends in Endocrinology and Metabolism (2018), 29 (1), 31-41CODEN: TENME4; ISSN:1043-2760. (Elsevier Ltd.)

     A review. Bile acids are endocrine mols. that in addn. to facilitating the absorption of fat-sol. nutrients regulate numerous metabolic processes, including glucose, lipid, and energy homeostasis. The signaling actions of bile acids are mediated through specific bile-acid-activated nuclear and membrane-bound receptors. These receptors are not only expressed by tissues within the enterohepatic circulation such as the liver and the intestine, but also in other organs wheree bile acids mediate their systemic actions. In this review, it has been discussed bile acid signaling and the interplay with the gut microbiota in the pathophysiol. of obesity, type 2 diabetes, and non-alc. fatty liver disease, and the role of surgical and pharmacol. interventions on bile acid profiles and metab.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvVKiu7jO&md5=77eb27c38818e3a42aca62f8b1638fe8

     
193. 193

     Hofmann, A. F. The Enterohepatic Circulation of Bile Acids in Mammals: Form and Functions. Front. Biosci., Landmark Ed. 2009, 14, 2584– 2598,  DOI: 10.2741/3399

     [Crossref], [PubMed], [CAS], Google Scholar

     193

     The enterohepatic circulation of bile acids in mammals: form and functions

     Hofmann, Alan F.

     Frontiers in Bioscience, Landmark Edition (2009), 14 (7), 2584-2598CODEN: FRBIF6; ISSN:1093-4715. (Frontiers in Bioscience)

     A review. The features of the enterohepatic circulation of bile acids in mammals are reviewed. Inputs into the circulating bile acids are primary bile acids synthesized from cholesterol in the hepatocyte and secondary bile acids formed by bacterial modification of primary bile acids in the distal intestine. Intestinal conservation of bile acids generates pools of individual bile acids whose relative sizes det. biliary bile acid compn. Efficient hepatic clearance results in low plasma bile acid levels, and virtually no renal excretion. Methods for characterizing the enterohepatic circulation are summarized. Bile acids have numerous physiol. functions in the liver, biliary tract, and intestine resulting from their signaling and physicochem. properties.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXltF2nsbc%253D&md5=79908d57e756691f0c5c2daa7c7c9db3

     
194. 194

     Dawson, P. A.; Haywood, J.; Craddock, A. L.; Wilson, M.; Tietjen, M.; Kluckman, K.; Maeda, N.; Parks, J. S. Targeted Deletion of the Ileal Bile Acid Transporter Eliminates Enterohepatic Cycling of Bile Acids in Mice. J. Biol. Chem. 2003, 278, 33920– 33927,  DOI: 10.1074/jbc.M306370200

     [Crossref], [PubMed], [CAS], Google Scholar

     194

     Targeted Deletion of the Ileal Bile Acid Transporter Eliminates Enterohepatic Cycling of Bile Acids in Mice

     Dawson, Paul A.; Haywood, Jamie; Craddock, Ann L.; Wilson, Martha; Tietjen, Mary; Kluckman, Kimberly; Maeda, Nobuyo; Parks, John S.

     Journal of Biological Chemistry (2003), 278 (36), 33920-33927CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)

     The ileal apical sodium bile acid cotransporter participates in the enterohepatic circulation of bile acids. In patients with primary bile acid malabsorption, mutations in the ileal bile acid transporter gene (Slc10a2) lead to congenital diarrhea, steatorrhea, and reduced plasma cholesterol levels. To elucidate the quant. role of Slc10a2 in intestinal bile acid absorption, the Slc10a2 gene was disrupted by homologous recombination in mice. Animals heterozygous (Slc10a2+/-) and homozygous (Slc10a2-/-) for this mutation were phys. indistinguishable from wild type mice. In the Slc10a2-/- mice, fecal bile acid excretion was elevated 10- to 20-fold and was not further increased by feeding a bile acid binding resin. Despite increased bile acid synthesis, the bile acid pool size was decreased by 80% and selectively enriched in cholic acid in the Slc10a2-/- mice. On a low fat diet, the Slc10a2-/- mice did not have steatorrhea. Fecal neutral sterol excretion was increased only 3-fold, and intestinal cholesterol absorption was reduced only 20%, indicating that the smaller cholic acid-enriched bile acid pool was sufficient to facilitate intestinal lipid absorption. Liver cholesteryl ester content was reduced by 50% in Slc10a2-/- mice, and unexpectedly plasma high d. lipoprotein cholesterol levels were slightly elevated. These data indicate that Slc10a2 is essential for efficient intestinal absorption of bile acids and that alternative absorptive mechanisms are unable to compensate for loss of Slc10a2 function.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXmvVCrtbY%253D&md5=0ea5404429e68e1e62b1f72c0f960134

     
195. 195

     Huang, H. C.; Tremont, S. J.; Lee, L. F.; Keller, B. T.; Carpenter, A. J.; Wang, C. C.; Banerjee, S. C.; Both, S. R.; Fletcher, T.; Garland, D. J.; Huang, W.; Jones, C.; Koeller, K. J.; Kolodziej, S. A.; Li, J.; Manning, R. E.; Mahoney, M. W.; Miller, R. E.; Mischke, D. A.; Rath, N. P.; Reinhard, E. J.; Tollefson, M. B.; Vernier, W. F.; Wagner, G. M.; Rapp, S. R.; Beaudry, J.; Glenn, K.; Regina, K.; Schuh, J. R.; Smith, M. E.; Trivedi, J. S.; Reitz, D. B. Discovery of Potent, Nonsystemic Apical Sodium-Codependent Bile Acid Transporter Inhibitors (Part 2). J. Med. Chem. 2005, 48, 5853– 5868,  DOI: 10.1021/jm0402162

     [ACS Full Text ], [CAS], Google Scholar

     195

     Discovery of Potent, Nonsystemic Apical Sodium-Codependent Bile Acid Transporter Inhibitors (Part 2)

     Huang, Horng-Chih; Tremont, Samuel J.; Lee, Len F.; Keller, Bradley T.; Carpenter, Andrew J.; Wang, Ching-Cheng; Banerjee, Shyamal C.; Both, Scott R.; Fletcher, Theresa; Garland, Danny J.; Huang, Wei; Jones, Claude; Koeller, Kevin J.; Kolodziej, Steve A.; Li, James; Manning, Robert E.; Mahoney, Matthew W.; Miller, Raymond E.; Mischke, Deborah A.; Rath, Nigam P.; Reinhard, Emily J.; Tollefson, Michael B.; Vernier, William F.; Wagner, Grace M.; Rapp, Steve R.; Beaudry, Judy; Glenn, Kevin; Regina, Karen; Schuh, Joe R.; Smith, Mark E.; Trivedi, Jay S.; Reitz, David B.

     Journal of Medicinal Chemistry (2005), 48 (18), 5853-5868CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

     Since the primary site for active bile acid reabsorption is via apical sodium-codependent bile acid transporter (ASBT), which is localized on the luminal surface of the distal ileum, a nonsystemic inhibitor would be desirable to minimize or eliminate potential systemic side effects of an absorbed drug. To ensure bioequivalency and product stability, it was also essential that a nonhygroscopic inhibitor in its most stable cryst. form was identified. A series of benzothiepins I [R = Ph, 4-HOC6H4, 4-(Me2NCH2CH2)C6H4, 1-naphthyl, 2-thienyl, 3-pyridyl, etc.] was prepd. to refine the structure-activity relationship of the substituted Ph ring at the 5-position of benzothiepin ring and to identify potent, cryst., nonhygroscopic, and efficacious ASBT inhibitors with low systemic exposure.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXntVChtrY%253D&md5=beeef9fb2676b3e2e7787b6dfbc75f7a

     
196. 196

     West, K. L.; Ramjiganesh, T.; Roy, S.; Keller, B. T.; Fernandez, M. L. 1-[4-[4[(4R,5R)-3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-di oxido-1-benzothiepin-5-yl]phenoxy]butyl]-4-aza-1-azoniabicyclo[2.2.2]octane Methanesulfonate (SC-435), an Ileal Apical Sodium-Codependent Bile Acid Transporter Inhibitor Alters Hepatic Cholesterol Metabolism and Lowers Plasma Low-Density Lipoprotein-Cholesterol Concentrations in Guinea Pigs. J. Pharmacol. Exp. Ther. 2002, 303, 293– 299,  DOI: 10.1124/jpet.102.038711

     [Crossref], [PubMed], [CAS], Google Scholar

     196

     1-[4-[4[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]butyl]-4-aza-1-azoniabicyclo[2.2.2]octane methanesulfonate (SC-435), an ileal apical sodium-codependent bile acid transporter inhibitor alters hepatic cholesterol metabolism and lowers plasma low-density lipoprotein-cholesterol concentrations in guinea pigs

     West, Kristy L.; Ramjiganesh, Tripurasundari; Roy, Suheeta; Keller, Bradley T.; Fernandez, Maria Luz

     Journal of Pharmacology and Experimental Therapeutics (2002), 303 (1), 293-299CODEN: JPETAB; ISSN:0022-3565. (American Society for Pharmacology and Experimental Therapeutics)

     Male Hartley guinea pigs (10/group) were assigned either to a control diet (no drug treatment) or to diets contg. 0.4, 2.2, or 7.3 mg/day of an ileal apical sodium-codependent bile acid transporter (ASBT) inhibitor, SC-435. Based on food consumption, guinea pigs received 0, 0.8, 3.7, or 13.4 mg/kg/day of the ASBT inhibitor. The amt. of cholesterol in the four diets was maintained at 0.17%, equiv. to 1200 mg/day in the human situation. Guinea pigs treated with 13.4 mg/kg/day SC-435 had 41% lower total cholesterol and 44% lower low-d. lipoprotein (LDL)-cholesterol concns. compared with control (P < 0.01), whereas no significant differences were obsd. with either of the lower doses of SC-435. Hepatic cholesterol esters were significantly reduced by 43, 56, and 70% in guinea pigs fed 0.8, 3.7, and 13.4 mg/kg/day of the ASBT inhibitor, resp. (P < 0.01). In addn., the highest dose of the inhibitor resulted in a 42% increase in the no. of very low-d. lipoprotein (VLDL) triacylglycerol mols. and a larger VLDL diam. compared with controls (P < 0.05). Acyl-CoA cholesterol/acyltransferase activity was 30% lower with the highest dose treatment, whereas cholesterol 7α-hydroxylase, the regulatory enzyme of bile acid synthesis, was 30% higher with the highest ASBT inhibitor dose (P < 0.05). Furthermore, bile acid excretion increased 2-fold with the highest dose of SC-435 compared with the control group (P < 0.05). These results suggest that the redn. in total and LDL-cholesterol concns. by the ASBT inhibitor is a result of alterations in hepatic cholesterol metab. due to modifications in the enterohepatic circulation of bile acids.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XnsV2qsbo%253D&md5=f0ac8d5a99a0acd0d81e39a8c63a54a1

     
197. 197

     Rao, A.; Kosters, A.; Mells, J. E.; Zhang, W.; Setchell, K. D.; Amanso, A. M.; Wynn, G. M.; Xu, T.; Keller, B. T.; Yin, H.; Banton, S.; Jones, D. P.; Wu, H.; Dawson, P. A.; Karpen, S. J. Inhibition of Ileal Bile Acid Uptake Protects Against Nonalcoholic Fatty Liver Disease in High-Fat Diet-Fed Mice. Sci. Transl. Med. 2016, 8, 357ra122,  DOI: 10.1126/scitranslmed.aaf4823

     [Crossref], [PubMed], Google Scholar

     There is no corresponding record for this reference.

     
198. 198

     Siebers, N.; Palmer, M.; Silberg, D. G.; Jennings, L.; Bliss, C.; Martin, P. T. Absorption, Distribution, Metabolism, and Excretion of [(14)C]-Volixibat in Healthy Men: Phase 1 Open-Label Study. Eur. J. Drug Metab. Pharmacokinet. 2018, 43, 91– 101,  DOI: 10.1007/s13318-017-0429-7

     [Crossref], [PubMed], [CAS], Google Scholar

     198

     Absorption, Distribution, Metabolism, and Excretion of [14C]-Volixibat in Healthy Men: Phase 1 Open-Label Study

     Siebers, Nicholas; Palmer, Melissa; Silberg, Debra G.; Jennings, Lee; Bliss, Caleb; Martin, Patrick T.

     European Journal of Drug Metabolism and Pharmacokinetics (2018), 43 (1), 91-101CODEN: EJDPD2; ISSN:0378-7966. (Springer France)

     Background and Objectives: Volixibat is a potent inhibitor of the apical sodium-dependent bile acid transporter in development for the treatment of nonalcoholic steatohepatitis. This phase 1, open-label study investigated the absorption, distribution, metab., and excretion of [14C]-volixibat in heathy men. Methods: Eligible men (n = 8) aged 18-50 years (body mass index 18.0-30.0 kg/m2; wt. >50 kg) received a single oral dose of [14C]-volixibat 50 mg contg. ∼5.95 μCi radioactivity. The primary objectives were to assess the pharmacokinetics of [14C]-volixibat and to det. the total radioactivity in whole blood, plasma, urine, and feces at pre-selected time points over 6 days. The secondary objectives were to characterize metabolites and to assess the safety and tolerability. Results: Low concns. of volixibat (range 0-0.179 ng/mL) were detected in plasma up to 8 h following administration; the pharmacokinetic parameters could not be calcd. No radioactivity was obsd. in plasma or whole blood. The percentage (mean ± std. deviation) of total radioactivity in urine was 0.01 ± 0.007%. The vast majority (92.3 ± 5.25%) of volixibat was recovered in feces (69.2 ± 33.1% within 24 h). Unchanged volixibat was the only radioactive component detected in feces. Adverse events were mild in severity and mostly gastrointestinal. Changes in lab. values were not clin. meaningful. Conclusions: Following oral administration, [14C]-volixibat was excreted unchanged from the parent compd. almost exclusively via fecal excretion, indicating that the drug is minimally absorbed. Consistent with other studies, adverse events were primarily gastrointestinal in nature. ClinicalTrials.gov identifier NCT02571192.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtFKmtLzL&md5=bdfd2285e44f55669ff32822bb61b4ca

     
199. 199

     Wong, B. S.; Camilleri, M. Elobixibat for the Treatment of Constipation. Expert Opin. Invest. Drugs 2013, 22, 277– 284,  DOI: 10.1517/13543784.2013.753056

     [Crossref], [PubMed], [CAS], Google Scholar

     199

     for the treatment of constipation

     Wong, Banny S.; Camilleri, Michael

     Expert Opinion on Investigational Drugs (2013), 22 (2), 277-284CODEN: EOIDER; ISSN:1354-3784. (Informa Healthcare)

     A review. Introduction: (formerly A3309) is a first-in-class ileal bile acid transporter (IBAT) inhibitor for treatment of chronic idiopathic constipation (CIC; syn functional constipation). CIC affects up to 25% of the general population; and up to a half are unsatisfied with current therapies. There is an unmet need for safe and effective drugs to treat CIC. Areas covered: The authors present: i) an overview of Phase II clin. trials of elobixibat in CIC, based on peer-reviewed literature and congress presentations and ii) an evaluation of the efficacy and mechanism of action of elobixibat in the treatment of CIC. Expert opinion: Elobixibat provides a novel approach to treat chronic constipation via IBAT inhibition with enhanced delivery of bile acids to the colon. Pharmacodynamic studies show that it accelerates colonic transit, increases stool frequency, loosens stool consistency and relieves constipation-related symptoms in CIC patients. These beneficial effects are maintained for a min. of 8 consecutive weeks of treatment. With minimal absorption and low systemic bioavailability, elobixibat is generally well tolerated and may offer the added benefit of improving serum lipid profiles through bile acid depletion.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXms12ksg%253D%253D&md5=9bcf6578bbeff0e220217b14209fc022

     
200. 200

     Yang, Q.; Zhang, Z.; Gregg, E. W.; Flanders, W. D.; Merritt, R.; Hu, F. B. Added Sugar Intake and Cardiovascular Diseases Mortality Among US Adults. JAMA Int. Med. 2014, 174, 516– 524,  DOI: 10.1001/jamainternmed.2013.13563

     [Crossref], [PubMed], [CAS], Google Scholar

     200

     Added sugar intake and cardiovascular diseases mortality among US adults

     Yang, Quanhe; Zhang, Zefeng; Gregg, Edward W.; Flanders, W. Dana; Merritt, Robert; Hu, Frank B.

     JAMA Internal Medicine (2014), 174 (4), 516-524, 9CODEN: JIMACF; ISSN:2168-6114. (American Medical Association)

     IMPORTANCE Epidemiol. studies have suggested that higher intake of added sugar is assocd. with cardiovascular disease (CVD) risk factors. Few prospective studies have examd. the assocn. of added sugar intake with CVD mortality. OBJECTIVE To examine time trends of added sugar consumption as percentage of daily calories in the United States and investigate the assocn. of this consumption with CVD mortality. DESIGN, SETTING, AND PARTICIPANTS National Health and Nutrition Examn. Survey (NHANES, 1988-1994 [III], 1999-2004, and 2005-2010 [n = 31 147]) for the time trend anal. and NHANES III Linked Mortality cohort (1988-2006 [n = 11 733]), a prospective cohort of a nationally representative sample of US adults for the assocn. study. MAIN OUTCOMES AND MEASURES Cardiovascular disease mortality. RESULTS Among US adults, the adjusted mean percentage of daily calories from added sugar increased from 15.7%(95%CI, 15.0%-16.4%) in 1988-1994 to 16.8%(16.0%-17.7%; P =.02) in 1999-2004 and decreased to 14.9%(14.2%-15.5%; P <.001) in 2005-2010. Most adults consumed 10% or more of calories from added sugar (71.4%) and approx. 10% consumed 25%or more in 2005-2010. During a median follow-up period of 14.6 years, we documented 831 CVD deaths during 163 039 person-years. Age-, sex-, and race/ethnicity- adjusted hazard ratios (HRs) of CVD mortality across quintiles of the percentage of daily calories consumed from added sugar were 1.00 (ref.), 1.09 (95%CI, 1.05-1.13), 1.23 (1.12-1.34), 1.49 (1.24-1.78), and 2.43 (1.63-3.62; P <.001), resp. After addnl. adjustment for sociodemog., behavioral, and clin. characteristics, HRs were 1.00 (ref.), 1.07 (1.02-1.12), 1.18 (1.06-1.31), 1.38 (1.11-1.70), and 2.03 (1.26-3.27; P =.004), resp. Adjusted HRs were 1.30 (95%CI, 1.09-1.55) and 2.75 (1.40-5.42; P =.004), resp., comparing participants who consumed 10.0%to 24.9% or 25.0%or more calories from added sugar with those who consumed less than 10.0%of calories from added sugar. These findings were largely consistent across age group, sex, race/ethnicity (except among non-Hispanic blacks), educational attainment, phys. activity, health eating index, and body mass index. CONCLUSIONS AND RELEVANCE Most US adults consume more added sugar than is recommended for a healthy diet.We obsd. a significant relationship between added sugar consumption and increased risk for CVD mortality.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhs1Snu7jP&md5=4548da54668f29dceb5d4b9983fecc15

     
201. 201

     Chan, T. F.; Lin, W. T.; Huang, H. L.; Lee, C. Y.; Wu, P. W.; Chiu, Y. W.; Huang, C. C.; Tsai, S.; Lin, C. L.; Lee, C. H. Consumption of Sugar-Sweetened Beverages is Associated with Components of the Metabolic Syndrome in Adolescents. Nutrients 2014, 6, 2088– 2103,  DOI: 10.3390/nu6052088

     [Crossref], [PubMed], [CAS], Google Scholar

     201

     Consumption of sugar-sweetened beverages is associated with components of the metabolic syndrome in adolescents

     Chan, Te-Fu; Lin, Wei-Ting; Huang, Hsiao-Ling; Lee, Chun-Ying; Wu, Pei-Wen; Chiu, Yu-Wen; Huang, Chun-Chi; Tsai, Sharon; Lin, Chih-Lung; Lee, Chien-Hung

     Nutrients (2014), 6 (5), 2088-2103, 16 pp.CODEN: NUTRHU; ISSN:2072-6643. (MDPI AG)

     Sugar-sweetened beverages (SSBs) are the principle source of added sugar in diets. Cardiometabolic disturbances can occur from early childhood to adulthood. The aim of this cross-sectional study was to examine the gender-specific assocn. of SSB intake with metabolic syndrome (MetS) and its components among adolescents in Taiwan. A total of 2727 adolescents aged 12 to 16 years randomly selected from three diverse economic areas in Southern Taiwan by using a multistage-sampling strategy participated in this study. Demog., dietary, phys. and anthropometric parameters were measured, and serum lipid profiles and glucose levels were detd. The International Diabetes Federation (IDF) specifies that MetS requires abdominal obesity and ≥2 abnormal components, and Cook criteria for MetS require ≥3 abnormal components. We applied survey-data modules to data analyses, and used multiple regression and logistic models to adjust for covariates. An increased SSB intake was linked to a greater waist circumference in both sexes and to systolic blood pressure in boys (P for trend: ≤0.043). Male moderate and high consuming SSB drinkers exhibited triglyceride levels that were 8.0 and 8.2 mg/dL significantly higher, resp., than those of nondrinkers. Compared with nondrinkers, boys who consumed >500 mL/day (high quantity) of SSBs exhibited 10.3-fold (95% confidence intervals (CIs): 1.2-90.2) and 5.1-fold (95% CIs: 1.01-25.5) risks of contracting MetS, as defined by the IDF and Cook criteria for MetS, resp. In girls, the risk ests. for the same comparison were not significant by the IDF criteria (6.5-fold risk, 95% CIs: 0.9-∞) or Cook criteria (5.9-fold risk, 95% CIs: 0.8-43.8) for MetS. High SSB consumption was also linked to 1.9-fold (95% CIs: 1.1-3.1) and 2.7-fold (95% CIs: 1.3-5.7) higher risks of being at a greater overall metabolic risk in girls and boys, resp. In conclusion, a high SSB intake is assocd. with adolescent MetS among boys but not girls in Taiwan.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhs1Glt7vL&md5=ffdbb5381e3ab42167dfff20c74cf643

     
202. 202

     Malik, V. S.; Popkin, B. M.; Bray, G. A.; Despres, J. P.; Willett, W. C.; Hu, F. B. Sugar-Sweetened Beverages and Risk of Metabolic Syndrome and Type 2 Diabetes: A Meta-Analysis. Diabetes Care 2010, 33, 2477– 2483,  DOI: 10.2337/dc10-1079

     [Crossref], [PubMed], [CAS], Google Scholar

     202

     Sugar-sweetened beverages and risk of metabolic syndrome and type 2 diabetes: a meta-analysis

     Malik Vasanti S; Popkin Barry M; Bray George A; Despres Jean-Pierre; Willett Walter C; Hu Frank B

     Diabetes care (2010), 33 (11), 2477-83 ISSN:.

     OBJECTIVE: Consumption of sugar-sweetened beverages (SSBs), which include soft drinks, fruit drinks, iced tea, and energy and vitamin water drinks has risen across the globe. Regular consumption of SSBs has been associated with weight gain and risk of overweight and obesity, but the role of SSBs in the development of related chronic metabolic diseases, such as metabolic syndrome and type 2 diabetes, has not been quantitatively reviewed. RESEARCH DESIGN AND METHODS: We searched the MEDLINE database up to May 2010 for prospective cohort studies of SSB intake and risk of metabolic syndrome and type 2 diabetes. We identified 11 studies (three for metabolic syndrome and eight for type 2 diabetes) for inclusion in a random-effects meta-analysis comparing SSB intake in the highest to lowest quantiles in relation to risk of metabolic syndrome and type 2 diabetes. RESULTS: Based on data from these studies, including 310,819 participants and 15,043 cases of type 2 diabetes, individuals in the highest quantile of SSB intake (most often 1-2 servings/day) had a 26% greater risk of developing type 2 diabetes than those in the lowest quantile (none or <1 serving/month) (relative risk [RR] 1.26 [95% CI 1.12-1.41]). Among studies evaluating metabolic syndrome, including 19,431 participants and 5,803 cases, the pooled RR was 1.20 [1.02-1.42]. CONCLUSIONS: In addition to weight gain, higher consumption of SSBs is associated with development of metabolic syndrome and type 2 diabetes. These data provide empirical evidence that intake of SSBs should be limited to reduce obesity-related risk of chronic metabolic diseases.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3cbis1Smuw%253D%253D&md5=1fbe66b34e8db160daa588fd0f90c92b

     
203. 203

     Ludwig, D. S.; Peterson, K. E.; Gortmaker, S. L. Relation Between Consumption of Sugar-Sweetened Drinks and Childhood Obesity: A Prospective, Observational Analysis. Lancet 2001, 357, 505– 508,  DOI: 10.1016/S0140-6736(00)04041-1

     [Crossref], [PubMed], [CAS], Google Scholar

     203

     Relation between consumption of sugar-sweetened drinks and childhood obesity: a prospective, observational analysis

     Ludwig D S; Peterson K E; Gortmaker S L

     Lancet (London, England) (2001), 357 (9255), 505-8 ISSN:0140-6736.

     BACKGROUND: The rising prevalence of obesity in children has been linked in part to the consumption of sugar-sweetened drinks. Our aim was to examine this relation. METHODS: We enrolled 548 ethnically diverse schoolchildren (age 11.7 years, SD 0.8) from public schools in four Massachusetts communities, and studied them prospectively for 19 months from October, 1995, to May, 1997. We examined the association between baseline and change in consumption of sugar-sweetened drinks (the independent variables), and difference in measures of obesity, with linear and logistic regression analyses adjusted for potentially confounding variables and clustering of results within schools. FINDINGS: For each additional serving of sugar-sweetened drink consumed, both body mass index (BMI) (mean 0.24 kg/m2; 95% CI 0.10-0.39; p=0.03) and frequency of obesity (odds ratio 1.60; 95% CI 1.14-2.24; p=0.02) increased after adjustment for anthropometric, demographic, dietary, and lifestyle variables. Baseline consumption of sugar-sweetened drinks was also independently associated with change in BMI (mean 0.18 kg/m2 for each daily serving; 95% CI 0.09-0.27; p=0.02). INTERPRETATION: Consumption of sugar-sweetened drinks is associated with obesity in children.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3M7lt1Shtw%253D%253D&md5=21eeac39590f5f9a6260cda42187c613

     
204. 204

     Assy, N.; Nasser, G.; Kamayse, I.; Nseir, W.; Beniashvili, Z.; Djibre, A.; Grosovski, M. Soft Drink Consumption Linked with Fatty Liver in the Absence of Traditional Risk Factors. Can. J. Gastroenterol. 2008, 22, 811– 816,  DOI: 10.1155/2008/810961

     [Crossref], [PubMed], [CAS], Google Scholar

     204

     Soft drink consumption linked with fatty liver in the absence of traditional risk factors

     Assy Nimer; Nasser Gattas; Kamayse Iad; Nseir William; Beniashvili Zaza; Djibre Agness; Grosovski Maria

     Canadian journal of gastroenterology = Journal canadien de gastroenterologie (2008), 22 (10), 811-6 ISSN:0835-7900.

     BACKGROUND: Little is known about dietary habits and their relationships with liver disease in nonalcoholic fatty liver disease (NAFLD) patients, particularly in the absence of obesity, diabetes or hyperlipidemia. OBJECTIVE: To assess the association between soft drink consumption and the presence of fatty liver in NAFLD patients who do not have classic risk factors. METHODS: Three hundred ten patients with NAFLD diagnosed by ultrasound were assessed for 36 months in a cross-sectional manner. Thirty-one patients (10%) who had NAFLD without classic risk factors were compared with 30 healthy controls. Physical activity was assessed during the preceding week and year, and every six months for 36 months. Data on daily dietary intake of food and soft drink, and the source of added sugar were collected during two seven-day periods, at the beginning of the study, and within two weeks after the metabolic tests by using a validated food questionnaire given by a trained dietician. Insulin resistance and lipid peroxidation were assessed by homeostasis model assessment-insulin resistance index (HOMA-IRI) and malondialdehyde (MDA) levels, respectively. RESULTS: Eighty per cent of patients (25 of 31) consumed an excessive amount of soft drink beverages (more than 50 g/day of added sugar) for 36 months, compared with 20% in healthy controls (P<0.001). Twenty per cent of patients consumed one drink per day, 40% consumed two to three drinks per day, and 40% consumed more than four drinks per day for most days during 36 months. The most common soft drinks consumed were regular Coca-Cola (40% of patients), Diet Coke (40%) and flavoured fruit juices (20%). Ultrasound findings revealed mild fatty liver in 44% of cases (n=14), moderate fatty liver in 38% (n=12), and severe fatty liver in 18% (n=5). HOMA-IRI and MDA levels were significantly higher in patients with NAFLD than in healthy controls (HOMA-IRI, 3.7 versus 1.7, P<0.001; and MDA, 420+/-300 micromol/mL versus 200+/-100 micromol/mL; P<0.001). When controlled for other factors, including dietary composition and physical activity, soft drink beverage consumption was the only independent variable that was able to predict the presence of fatty liver in 82.5% of cases with a sensitivity of 100%, a specificity of 76%, a positive predictive value of 57% and a negative predictive value of 100%. CONCLUSION: The present study may add important insight into the role of sugar-sweetened beverage consumption as a cause of fatty liver in patients without risk factors. Patients are encouraged to change their long-standing drinking behaviour.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1cnms1Wqsw%253D%253D&md5=64201069a40bf629800a1c96179fb12c

     
205. 205

     Abid, A.; Taha, O.; Nseir, W.; Farah, R.; Grosovski, M.; Assy, N. Soft Drink Consumption is Associated with Fatty Liver Disease Independent of Metabolic Syndrome. J. Hepatol. 2009, 51, 918– 924,  DOI: 10.1016/j.jhep.2009.05.033

     [Crossref], [PubMed], [CAS], Google Scholar

     205

     Soft drink consumption is associated with fatty liver disease independent of metabolic syndrome

     Abid, Ali; Taha, Ola; Nseir, William; Farah, Raymond; Grosovski, Maria; Assy, Nimer

     Journal of Hepatology (2009), 51 (5), 918-924CODEN: JOHEEC; ISSN:0168-8278. (Elsevier B.V.)

     Background/Aims: The independent role of soft drink consumption in non-alc. fatty liver disease (NAFLD) patients remains unclear. We aimed to assess the assocn. between consumption of soft drinks and fatty liver in patients with or without metabolic syndrome. Methods: We recruited 31 patients (age: 43 ± 12 years) with NAFLD and risk factors for metabolic syndrome, 29 patients with NAFLD and without risk factors for metabolic syndrome, and 30 gender- and age-matched individuals without NAFLD. The degree of fatty infiltration was measured by ultrasound. Data on phys. activity and intake of food and soft drinks were collected during two 7-day periods over 6 mo using a food questionnaire. Insulin resistance, inflammation, and oxidant-antioxidant markers were measured. Results: We found that 80% of patients with NAFLD had excessive intake of soft drink beverages (>500 cm3/day) compared to 17% of healthy controls (p < 0.001). The NAFLD group consumed five times more carbohydrates from soft drinks compared to healthy controls (40% vs. 8%, p < 0.001). Seven percent of patients consumed one soft drink per day, 55% consumed two or three soft drinks per day, and 38% consumed more than four soft drinks per day for most days and for the 6-mo period. The most common soft drinks were Coca-Cola (regular: 32%; diet: 21%) followed by fruit juices (47%). Patients with NAFLD with metabolic syndrome had similar malonyldialdehyde, paraoxonase, and C-reactive protein (CRP) levels but higher homeostasis model assessment (HOMA) and higher ferritin than NAFLD patients without metabolic syndrome (HOMA: 8.3 ± 8 vs. 3.7 ± 3.7 mg/dL, p < 0.001; ferritin: 186 ± 192 vs. 87 ± 84 mg/dL, p < 0.01). Logistic regression anal. showed that soft drink consumption is a strong predictor of fatty liver (odds ratio: 2.0; p < 0.04) independent of metabolic syndrome and CRP level. Conclusions: NAFLD patients display higher soft drink consumption independent of metabolic syndrome diagnosis. These findings might optimize NAFLD risk stratification.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXht1CqurvM&md5=3d004438b6f78fc3a33d11c058d2ebd4

     
206. 206

     Bonthron, D. T.; Brady, N.; Donaldson, I. A.; Steinmann, B. Molecular Basis of Essential Fructosuria: Molecular Cloning and Mutational Analysis of Human Ketohexokinase (Fructokinase). Hum. Mol. Genet. 1994, 3, 1627– 1631,  DOI: 10.1093/hmg/3.9.1627

     [Crossref], [PubMed], [CAS], Google Scholar

     206

     Molecular basis of essential fructosuria: molecular cloning and mutational analysis of human ketohexokinase (fructokinase)

     Bonthron, David T.; Brady, Nicola; Donaldson, Iain A.; Steinmann, Beat

     Human Molecular Genetics (1994), 3 (9), 1627-31CODEN: HMGEE5; ISSN:0964-6906.

     Essential fructosuria is one of the oldest known inborn errors of metab. It is a benign condition which is believed to result from deficiency of hepatic fructokinase (ketohexokinase, KHK, E.C.2.7.1.3.). This enzyme catalyzes the first step of metab. of dietary fructose, conversion of fructose to fructose-1-phosphate. Despite the early recognition of this disorder, the primary structure of human KHK and the mol. basis of essential fructosuria have not been previously defined. In this report, the isolation and sequencing of full-length cDNA clones encoding human ketohexokinase are described. Alternative mRNA species and alternative KHK isoenzymes are produced by alternative polyadenylation and splicing of the KHK gene. The KHK proteins show a high level of sequence conservation relative to rat KHK. Direct evidence that mutation of the KHK structural gene is the cause of essential fructosuria was also obtained. In a well-characterized family, in which 3 of 8 siblings have fructosuria, all affected individuals are compd. heterozygotes for 2 mutations Gly40Arg and Ala43Thr. Both mutations result from G→A transitions, and each alters the same conserved region of the KHK protein. Neither mutation was seen in a sample of 52 unrelated control individuals. An addnl. conservative amino acid change (Val49IIe) was present on the KHK allele bearing Ala43Thr.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXhtVGnt78%253D&md5=1e3f908a2d87d3a49c4897aa84ac3345

     
207. 207

     Ishimoto, T.; Lanaspa, M. A.; Le, M. T.; Garcia, G. E.; Diggle, C. P.; Maclean, P. S.; Jackman, M. R.; Asipu, A.; Roncal-Jimenez, C. A.; Kosugi, T.; Rivard, C. J.; Maruyama, S.; Rodriguez-Iturbe, B.; Sanchez-Lozada, L. G.; Bonthron, D. T.; Sautin, Y. Y.; Johnson, R. J. Opposing Effects of Fructokinase C and A Isoforms on Fructose-Induced Metabolic Syndrome in Mice. Proc. Natl. Acad. Sci. U. S. A. 2012, 109, 4320– 4325,  DOI: 10.1073/pnas.1119908109

     [Crossref], [PubMed], [CAS], Google Scholar

     207

     Opposing effects of fructokinase C and A isoforms on fructose-induced metabolic syndrome in mice

     Ishimoto, Takuji; Lanaspa, Miguel A.; Le, My Phuong T.; Garcia, Gabriela E.; Diggle, Christine P.; MacLean, Paul S.; Jackman, Matthew R.; Asipu, Aruna; Roncal-Jimenez, Carlos A.; Kosugi, Tomoki; Rivard, Christopher J.; Maruyama, Shoichi; Rodriguez-Iturbe, Bernardo; Snchez-Lozada, Laura G.; Bonthron, David T.; Sautin, Yuri Y.; Johnson, Richard J.

     Proceedings of the National Academy of Sciences of the United States of America (2012), 109 (11), 4320-4325, S4320/1-S4320/5CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)

     Fructose intake from added sugars correlates with the epidemic rise in obesity, metabolic syndrome, and nonalcoholic fatty liver disease. Fructose intake also causes features of metabolic syndrome in lab. animals and humans. The first enzyme in fructose metab. is fructokinase, which exists as two isoforms, A and C. Here we show that fructose-induced metabolic syndrome is prevented in mice lacking both isoforms but is exacerbated in mice lacking fructokinase A. Fructokinase C is expressed primarily in liver, intestine, and kidney and has high affinity for fructose, resulting in rapid metab. and marked ATP depletion. In contrast, fructokinase A is widely distributed, has low affinity for fructose, and has less dramatic effects on ATP levels. By reducing the amt. of fructose for metab. in the liver, fructokinase A protects against fructokinase C-mediated metabolic syndrome. These studies provide insights into the mechanisms by which fructose causes obesity and metabolic syndrome.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XkslGltbc%253D&md5=fd8c85c10a00df73910e0937a4220b47

     
208. 208

     Schlappal, A.; Geller, E.; Castonguay, T. Fructose-Induced Hypertriglyceridemia: A Review. In Nutrition in the Prevention and Treatment of Abdominal Obesity; Watson, R., Ed.; Academic Press: London, UK, 2014; pp 197– 205.

     Google Scholar

     There is no corresponding record for this reference.

     
209. 209

     Schwarz, J. M.; Noworolski, S. M.; Wen, M. J.; Dyachenko, A.; Prior, J. L.; Weinberg, M. E.; Herraiz, L. A.; Tai, V. W.; Bergeron, N.; Bersot, T. P.; Rao, M. N.; Schambelan, M.; Mulligan, K. Effect of a High-Fructose Weight-Maintaining Diet on Lipogenesis and Liver Fat. J. Clin. Endocrinol. Metab. 2015, 100, 2434– 2442,  DOI: 10.1210/jc.2014-3678

     [Crossref], [PubMed], [CAS], Google Scholar

     209

     Effect of a high-fructose weight-maintaining diet on lipogenesis and liver fat

     Schwarz, Jean-Marc; Noworolski, Susan M.; Wen, Michael J.; Dyachenko, Artem; Prior, Jessica L.; Weinberg, Melissa E.; Herraiz, Laurie A.; Tai, Viva W.; Bergeron, Nathalie; Bersot, Thomas P.; Rao, Madhu N.; Schambelan, Morris; Mulligan, Kathleen

     Journal of Clinical Endocrinology and Metabolism (2015), 100 (6), 2434-2442CODEN: JCEMAZ; ISSN:0021-972X. (Endocrine Society)

     Context: Consumption of high-fructose diets promotes hepatic fatty acid synthesis (de novo lipogenesis [DNL]) and an atherogenic lipid profile. It is unclear whether these effects occur independent of pos. energy balance and wt. gain. Objectives: We compared the effects of a high-fructose, (25% of energy content) wt.-maintaining diet to those of an isocaloric diet with the same macronutrient distribution but in which complex carbohydrate (CCHO) was substituted for fructose. Design, Setting, and Participants: Eight healthy men were studied as inpatients for consecutive 9-day periods. Stable isotope tracers were used to measure fractional hepatic DNL and endogenous glucose prodn. (EGP) and its suppression during a euglycemic-hyperinsulinemic clamp. Liver fat was measured by magnetic resonance spectroscopy. Results: Wt. remained stable. Regardless of the order in which the diets were fed, the high-fructose diet was assocd. with both higher DNL (av., 18.6 ± 1.4% vs 11.0 ± 1.4% for CCHO; P = .001) and higher liver fat (median, +137% of CCHO; P = .016) in all participants. Fasting EGP and insulin-mediated glucose disposal did not differ significantly, but EGP during hyperinsulinemia was greater (0.60 ± 0.07 vs 0.46 ± 0.06 mg/kg/min; P = .013) with the high-fructose diet, suggesting blunted suppression of EGP. Conclusion: Short-term high-fructose intake was assocd. with increased DNL and liver fat in healthy men fed wt.-maintaining diets.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtVOru7fO&md5=ce05c14d39d8b6e743eaeff71b3c18ed

     
210. 210

     Marek, G.; Pannu, V.; Shanmugham, P.; Pancione, B.; Mascia, D.; Crosson, S.; Ishimoto, T.; Sautin, Y. Y. Adiponectin Resistance and Proinflammatory Changes in the Visceral Adipose Tissue Induced by Fructose Consumption via Ketohexokinase-Dependent Pathway. Diabetes 2015, 64, 508– 518,  DOI: 10.2337/db14-0411

     [Crossref], [PubMed], [CAS], Google Scholar

     210

     Adiponectin resistance and proinflammatory changes in the visceral adipose tissue induced by fructose consumption via ketohexokinase-dependent pathway

     Marek, George; Pannu, Varinderpal; Shanmugham, Prashanth; Pancione, Brianna; Mascia, Dominic; Crosson, Sean; Ishimoto, Takuji; Sautin, Yuri Y.

     Diabetes (2015), 64 (2), 508-518CODEN: DIAEAZ; ISSN:0012-1797. (American Diabetes Association, Inc.)

     An epidemic of obesity and type 2 diabetes is linked with the increase in consumption of fructose-contg. sugars, such as sucrose and high-fructose corn syrup. In mammalian cells, fructose is metabolized predominantly via phosphorylation to fructose-1 phosphate by ketohexokinase (KHK) or by alternative pathways. Here we demonstrate that a KHK-dependent pathway mediates insulin resistance and inflammatory changes in the visceral fat in response to high fructose. We used mice (males, C57BL/6 background) including littermate wild-type control and mice lacking both isoforms of KHK (KHK-null). Fructose diet induced metabolic syndrome, including visceral obesity, insulin resistance, proinflammatory changes in the visceral fat (prodn. of proinflammatory adipokines and macrophage infiltration), the endoplasmic reticulum stress signaling, and decrease of the high-mol. wt. adiponectin followed by decrease in the downstream signaling. KHK-KO mice consuming the same high-fructose diet remained lean, with normal insulin sensitivity and healthy visceral adipose tissue with normal adiponectin function not distinguishable from the control by any of the tested parameters. This study demonstrates that blocking KHK and redirecting fructose metab. to alternative pathways is an effective way to prevent visceral obesity and insulin resistance induced by high fructose, a widespread component of Western diets.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXislGhtLo%253D&md5=513c39c853de1eeb46805d5d7c036482

     
211. 211

     Lanaspa, M. A.; Andres-Hernando, A.; Orlicky, D. J.; Cicerchi, C.; Jang, C.; Li, N.; Milagres, T.; Kuwabara, M.; Wempe, M. F.; Rabinowitz, J. D.; Johnson, R. J.; Tolan, D. R. Ketohexokinase C Blockade Ameliorates Fructose-Induced Metabolic Dysfunction in Fructose-Sensitive Mice. J. Clin. Invest. 2018, 128, 2226– 2238,  DOI: 10.1172/JCI94427

     [Crossref], [PubMed], [CAS], Google Scholar

     211

     Ketohexokinase C blockade ameliorates fructose-induced metabolic dysfunction in fructose-sensitive mice

     Lanaspa Miguel A; Andres-Hernando Ana; Orlicky David J; Cicerchi Christina; Li Nanxing; Milagres Tamara; Kuwabara Masanari; Johnson Richard J; Jang Cholsoon; Rabinowitz Joshua D; Wempe Michael F; Tolan Dean R

     The Journal of clinical investigation (2018), 128 (6), 2226-2238 ISSN:.

     Increasing evidence suggests a role for excessive intake of fructose in the Western diet as a contributor to the current epidemics of metabolic syndrome and obesity. Hereditary fructose intolerance (HFI) is a difficult and potentially lethal orphan disease associated with impaired fructose metabolism. In HFI, the deficiency of aldolase B results in the accumulation of intracellular phosphorylated fructose, leading to phosphate sequestration and depletion, increased adenosine triphosphate (ATP) turnover, and a plethora of conditions that lead to clinical manifestations such as fatty liver, hyperuricemia, Fanconi syndrome, and severe hypoglycemia. Unfortunately, there is currently no treatment for HFI, and avoiding sugar and fructose has become challenging in our society. In this report, through use of genetically modified mice and pharmacological inhibitors, we demonstrate that the absence or inhibition of ketohexokinase (Khk), an enzyme upstream of aldolase B, is sufficient to prevent hypoglycemia and liver and intestinal injury associated with HFI. Herein we provide evidence for the first time to our knowledge of a potential therapeutic approach for HFI. Mechanistically, our studies suggest that it is the inhibition of the Khk C isoform, not the A isoform, that protects animals from HFI.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1Mngs1Siug%253D%253D&md5=163a6ff28c27ccb0f778e35db46e3d35

     
212. 212

     Sachs, B. Essential Fructosuria. AMA Am. J. Dis. Child. 1942, 63, 252– 269,  DOI: 10.1001/archpedi.1942.02010020037004

     [Crossref], [CAS], Google Scholar

     212

     Essential fructosuria. Its pathophysiology

     Sachs, Benjamin; Sternfeld, Leon; Kraus, George

     American Journal of Diseases of Children (1942), 63 (), 252-69CODEN: AJDCAI; ISSN:0002-922X.

     Tests of kidney and liver function were normal in the 2 cases of essential fructosuria studied. After ingestion of fructose there was little rise in the lactic acid content of the blood of the patients while that of normal individuals rose appreciably. The mechanism for fructosuria appears to lie in the failure of part of the ingested fructose to be broken down to lactic acid. A tabular review of 55 cases reported in the literature is presented.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaH38XitlSktg%253D%253D&md5=3178112bf02c60846edee1ba6a27c201

     
213. 213

     Gibbs, A. C.; Abad, M. C.; Zhang, X.; Tounge, B. A.; Lewandowski, F. A.; Struble, G. T.; Sun, W.; Sui, Z.; Kuo, L. C. Electron Density Guided Fragment-Based Lead Discovery of Ketohexokinase Inhibitors. J. Med. Chem. 2010, 53, 7979– 7991,  DOI: 10.1021/jm100677s

     [ACS Full Text ], [CAS], Google Scholar

     213

     Electron Density Guided Fragment-Based Lead Discovery of Ketohexokinase Inhibitors

     Gibbs, Alan C.; Abad, Marta C.; Zhang, Xuqing; Tounge, Brett A.; Lewandowski, Francis A.; Struble, Geoffrey T.; Sun, Weimei; Sui, Zhihua; Kuo, Lawrence C.

     Journal of Medicinal Chemistry (2010), 53 (22), 7979-7991CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

     A fragment-based drug design paradigm has been successfully applied in the discovery of lead series of ketohexokinase inhibitors. The paradigm consists of three iterations of design, synthesis, and x-ray crystallog. screening to progress low mol. wt. fragments to leadlike compds. Applying electron d. of fragments within the protein binding site as defined by x-ray crystallog., one can generate target specific leads without the use of affinity data. Our approach contrasts with most fragment-based drug design methodol. where soln. activity is a main design guide. Herein we describe the discovery of submicromolar ketohexokinase inhibitors with promising druglike properties.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtlGntr%252FF&md5=3abdf4ac63d4afcf6a4db484d0d87259

     
214. 214

     Maryanoff, B. E.; O’Neill, J. C.; McComsey, D. F.; Yabut, S. C.; Luci, D. K.; Jordan, A. D., Jr.; Masucci, J. A.; Jones, W. J.; Abad, M. C.; Gibbs, A. C.; Petrounia, I. Inhibitors of Ketohexokinase: Discovery of Pyrimidinopyrimidines with Specific Substitution that Complements the ATP-Binding Site. ACS Med. Chem. Lett. 2011, 2, 538– 543,  DOI: 10.1021/ml200070g

     [ACS Full Text ], [CAS], Google Scholar

     214

     Inhibitors of Ketohexokinase: Discovery of Pyrimidinopyrimidines with Specific Substitution that Complements the ATP-Binding Site

     Maryanoff, Bruce E.; O'Neill, John C.; McComsey, David F.; Yabut, Stephen C.; Luci, Diane K.; Jordan, Alfonzo D.; Masucci, John A.; Jones, William J.; Abad, Marta C.; Gibbs, Alan C.; Petrounia, Ioanna

     ACS Medicinal Chemistry Letters (2011), 2 (7), 538-543CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)

     Attenuation of fructose metab. by the inhibition of ketohexokinase (KHK; fructokinase) should reduce body wt., free fatty acids, and triglycerides, thereby offering a novel approach to treat diabetes and obesity in response to modern diets. We have identified potent, selective inhibitors of human hepatic KHK within a series of pyrimidinopyrimidines (1). For example, 8, 38, and 47 exhibited KHK IC50 values of 12, 7, and 8 nM, resp., and also showed potent cellular KHK inhibition (IC50 < 500 nM), which relates to their intrinsic potency vs KHK and their ability to penetrate cells. X-ray cocrystal structures of KHK complexes of 3, 8, and 47 revealed the important interactions within the enzyme's ATP-binding pocket.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXltlGhsr8%253D&md5=8ed0465ad9571e67ac226935994fa5fb

     
215. 215

     Zhang, X.; Song, F.; Kuo, G. H.; Xiang, A.; Gibbs, A. C.; Abad, M. C.; Sun, W.; Kuo, L. C.; Sui, Z. Optimization of a Pyrazole Hit From FBDD into a Novel Series of Indazoles as Ketohexokinase Inhibitors. Bioorg. Med. Chem. Lett. 2011, 21, 4762– 4767,  DOI: 10.1016/j.bmcl.2011.06.067

     [Crossref], [PubMed], [CAS], Google Scholar

     215

     Optimization of a pyrazole hit from FBDD into a novel series of indazoles as ketohexokinase inhibitors

     Zhang, Xuqing; Song, Fengbing; Kuo, Gee-Hong; Xiang, Amy; Gibbs, Alan C.; Abad, Marta C.; Sun, Weimei; Kuo, Lawrence C.; Sui, Zhihua

     Bioorganic & Medicinal Chemistry Letters (2011), 21 (16), 4762-4767CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)

     A series of indazoles, e.g. I-III, have been discovered as KHK inhibitors from a pyrazole hit identified through fragment-based drug discovery (FBDD). The optimization process guided by both X-ray crystallog. and soln. activity resulted in lead-like compds. with good pharmaceutical properties.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXps1Snu74%253D&md5=80b3561f1d3ef419c2ec3a4d7dc3154d

     
216. 216

     Huard, K.; Ahn, K.; Amor, P.; Beebe, D. A.; Borzilleri, K. A.; Chrunyk, B. A.; Coffey, S. B.; Cong, Y.; Conn, E. L.; Culp, J. S.; Dowling, M. S.; Gorgoglione, M. F.; Gutierrez, J. A.; Knafels, J. D.; Lachapelle, E. A.; Pandit, J.; Parris, K. D.; Perez, S.; Pfefferkorn, J. A.; Price, D. A.; Raymer, B.; Ross, T. T.; Shavnya, A.; Smith, A. C.; Subashi, T. A.; Tesz, G. J.; Thuma, B. A.; Tu, M.; Weaver, J. D.; Weng, Y.; Withka, J. M.; Xing, G.; Magee, T. V. Discovery of Fragment-Derived Small Molecules for in Vivo Inhibition of Ketohexokinase (KHK). J. Med. Chem. 2017, 60, 7835– 7849,  DOI: 10.1021/acs.jmedchem.7b00947

     [ACS Full Text ], [CAS], Google Scholar

     216

     Discovery of Fragment-Derived Small Molecules for in Vivo Inhibition of Ketohexokinase (KHK)

     Huard, Kim; Ahn, Kay; Amor, Paul; Beebe, David A.; Borzilleri, Kris A.; Chrunyk, Boris A.; Coffey, Steven B.; Cong, Yang; Conn, Edward L.; Culp, Jeffrey S.; Dowling, Matthew S.; Gorgoglione, Matthew F.; Gutierrez, Jemy A.; Knafels, John D.; Lachapelle, Erik A.; Pandit, Jayvardhan; Parris, Kevin D.; Perez, Sylvie; Pfefferkorn, Jeffrey A.; Price, David A.; Raymer, Brian; Ross, Trenton T.; Shavnya, Andre; Smith, Aaron C.; Subashi, Timothy A.; Tesz, Gregory J.; Thuma, Benjamin A.; Tu, Meihua; Weaver, John D.; Weng, Yan; Withka, Jane M.; Xing, Gang; Magee, Thomas V.

     Journal of Medicinal Chemistry (2017), 60 (18), 7835-7849CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

     Increased fructose consumption and its subsequent metab. have been implicated in hepatic steatosis, dyslipidemia, obesity, and insulin resistance in humans. Since ketohexokinase (KHK) is the principal enzyme responsible for fructose metab., identification of a selective KHK inhibitor may help to further elucidate the effect of KHK inhibition on these metabolic disorders. Until now, studies on KHK inhibition with small mols. have been limited due to the lack of viable in vivo pharmacol. tools. Herein the authors report the discovery of 12 (6-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)-2-((S)-3-hydroxy-3-methylpyrrolidin-1-yl)-4-(trifluoromethyl)nicotinonitrile), a selective KHK inhibitor with potency and properties suitable for evaluating KHK inhibition in rat models. Key structural features interacting with KHK were discovered through fragment-based screening and subsequent optimization using structure-based drug design, and parallel medicinal chem. led to the identification of pyridine 12.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsVagu7jK&md5=d83bc39986e54a0f41e8f310b725ab92

     
217. 217

     Dowling, M.; Fernando, D.; Futatsugi, K.; Huard, K.; Magee, T. V. Substituted 3-Azabicyclo[3.1.0]hexanes as Ketohexokinase Inhibitors. International Patent WO2017115205, 2017.

     Google Scholar

     There is no corresponding record for this reference.

     
218. 218

     Calle, R.; Bergman, A.; Somayaji, V.; Chisey, K.; Kazierd, D. Ketohexokinase Inhibitor PF-06835919 Administered for 6 Weeks Reduces Whole Liver Fat as Measured by Magnetic Resonance Imaging-Proton Density Fat Fraction in Subjects with Non-Alcoholic Fatty Liver Disease. Presented at the European Associate for the Study of the Liver International Liver Conference, Vienna, Austria, April 10–14, 2019; PS-110.

     Google Scholar

     There is no corresponding record for this reference.

     
219. 219

     Campos, R. V.; Lee, Y. C.; Drucker, D. J. Divergent Tissue-Specific and Developmental Expression of Receptors for Glucagon and Glucagon-Like Peptide-1 in the Mouse. Endocrinology 1994, 134, 2156– 2164,  DOI: 10.1210/endo.134.5.8156917

     [Crossref], [PubMed], [CAS], Google Scholar

     219

     Divergent tissue-specific and developmental expression of receptors for glucagon and glucagon-like peptide-1 in the mouse

     Campos, Robert V.; Lee, Ying C.; Drucker, Daniel J.

     Endocrinology (1994), 134 (5), 2156-64CODEN: ENDOAO; ISSN:0013-7227.

     Proglucagon mRNA transcripts are transcribed in the pancreas, bowel, and brain, after which posttranslational processing results in the liberation of a different profile of biol. active peptides in each tissue. The receptors of two of these peptides, glucagon and glucagon-like peptide-1 (GLP-1), have recently been identified, but only limited information is available concerning the tissue- and age-specific distribution of these receptors in vivo. The authors have investigated the expression of these receptors in the mouse using a combination of Northern blot anal. and reverse transcription-polymerase chain reaction. DNA sequence anal. of a partial mouse glucagon receptor cDNA demonstrated a high degree of sequence conservation across rodent species. Glucagon receptor mRNA transcripts were detectable by Northern blotting in poly(A)+ RNA from liver and kidney. Reverse transcription-polymerase chain reaction also detected glucagon receptor mRNA transcripts in both fetal and adult pancreas and lung, jejunum, and ileum, but not in the large intestine. In contrast, mRNA transcripts for the GLP-1 receptor were detected in both small and large intestine as well as in pancreas, liver, lung, and kidney. Both glucagon and GLP-1 receptor mRNA transcripts were identified in different regions of the fetal and adult mouse brain, but the relative levels of GLP-1 receptor mRNA transcripts were much greater in the central nervous system. Furthermore, regulation of the GLP-1 receptor (but not the glucagon receptor) gene in the brain resembled the pattern of region-specific gene expression recently defined for the mouse proglucagon gene. Taken together, these studies define novel sites for both glucagon and GLP-1 receptor gene expression in the mouse and suggest that different regulatory mechanisms have evolved for tissue-specific and developmental control of receptor gene expression.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2cXktVantLk%253D&md5=8f95852afff38b48c3b6847ac4fad389

     
220. 220

     Bullock, B. P.; Heller, R. S.; Habener, J. F. Tissue Distribution of Messenger Ribonucleic Acid Encoding the Rat Glucagon-Like Peptide-1 Receptor. Endocrinology 1996, 137, 2968– 2978,  DOI: 10.1210/endo.137.7.8770921

     [Crossref], [PubMed], [CAS], Google Scholar

     220

     Tissue distribution of messenger ribonucleic acid encoding the rat glucagon-like peptide-1 receptor

     Bullock, Bryant P.; Heller, R. Scott; Habener, Joel F.

     Endocrinology (1996), 137 (7), 2968-2978CODEN: ENDOAO; ISSN:0013-7227. (Endocrine Society)

     The incretin hormone glucagon-like peptide-1 (GLP-1) is an important regulator of postprandial insulin secretion. In addn. to its insulinotropic actions on pancreatic β-cells, GLP-1 enhances glucose disposal by insulin-independent mechanisms, suggesting that GLP-1 receptors are located on extrapancreatic tissues. In this study, we examd. the tissue distribution of GLP-1 receptor (GLP-1R) mRNA in rat by RNAse protection, RT-PCR, and in situ hybridization. We identified GLP-1R mRNA in the lung, pancreatic islets, stomach, and kidney by the RNAse protection assay. RT-PCR anal. also detected GLP-1R mRNA in the hypothalamus and heart. In situ hybridization expts. identified receptor mRNA in the gastric pits of the stomach, large nucleated cells in the lung, crypts of the duodenum, and pancreatic islets. No localized specific grains were found in kidney, skeletal muscle, heart, liver, or adipocytes. These results indicate that sequences corresponding to the cloned rat islet GLP-1 receptor are expressed in the pancreatic islets, lung, hypothalamus, stomach, heart, and kidney but not in adipose, liver, and skeletal muscle. Further, the GLP-1 receptor expressed in the kidney and heart may be structural variants of the known receptor. Therefore, the obsd. extrapancreatic actions of GLP-1 may not be strictly confined to interactions with the defined GLP-1 receptor.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XjvVWjtLo%253D&md5=743b695bb2ca16257d0f9a5a61aaf387

     
221. 221

     Tornehave, D.; Kristensen, P.; Romer, J.; Knudsen, L. B.; Heller, R. S. Expression of the GLP-1 Receptor in Mouse, Rat, and Human Pancreas. J. Histochem. Cytochem. 2008, 56, 841– 851,  DOI: 10.1369/jhc.2008.951319

     [Crossref], [PubMed], [CAS], Google Scholar

     221

     Expression of the GLP-1 receptor in mouse, rat, and human pancreas

     Tornehave, Ditte; Kristensen, Peter; Roemer, John; Knudsen, Lotte Bjerre; Heller, R. Scott

     Journal of Histochemistry and Cytochemistry (2008), 56 (9), 841-851CODEN: JHCYAS; ISSN:0022-1554. (Histochemical Society, Inc.)

     We studied the intra-islet localization of the glucagon-like peptide 1 receptor (GLP-1R) by colocalization studies of the GLP-1R mRNA and protein with islet cell hormones in mice, rats, and humans. In contrast to previous reports, we show that the GLP-1R is selectively located on the β cells. The localization of GLP-1R in islets and ducts was studied using ISH and double and triple fluorescence microscopy. In normal pancreatic tissue from mice and rats, GLP-1R mRNA was only detectable in the β cells. Double and triple immunofluorescence using two different GLP-1R antisera and combinations of insulin, glucagon, pancreatic polypeptide, and somatostatin showed that GLP-1R protein is almost exclusively colocalized with insulin. The same pattern was obsd. in human pancreas, but the GLP-1R expression was more heterogeneous, with populations of insulin immunoreactive cells with high and low expression. This is the first time that the GLP-1R has been localized in human islets. Furthermore, GLP-1R immunoreactivity was found in the pancreatic ducts in mouse, rat, and human pancreas. As an important confirmation of the specificity of our methods, we found no signals for GLP-1R mRNA or protein in pancreatic tissue from gene-targeted GLP-1R-deficient mice. In conclusion, our data suggest that the GLP-1 receptor is restricted to the pancreatic β cells and the lack of receptor immunoreactivity on δ cells cannot be explained suitably to correspond with published in vivo and in vitro data.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXpvFOjsr8%253D&md5=292f42c47af0d455f821a0fa32e4a52e

     
222. 222

     Parker, H. E.; Reimann, F.; Gribble, F. M. Molecular Mechanisms Underlying Nutrient-Stimulated Incretin Secretion. Expert Rev. Mol. Med. 2010, 12, e1  DOI: 10.1017/S146239940900132X

     [Crossref], [PubMed], [CAS], Google Scholar

     222

     Molecular mechanisms underlying nutrient-stimulated incretin secretion

     Parker, Helen E.; Reimann, Frank; Gribble, Fiona M.

     Expert Reviews in Molecular Medicine (2010), 12 (), e1/1-e1/17CODEN: ERMMFS; ISSN:1462-3994. (Cambridge University Press)

     A review. The incretin hormones glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are released from enteroendocrine cells in the intestinal epithelium in response to nutrient ingestion. The actions of GLP-1 and GIP - not only on local gut physiol. but also on glucose homeostasis, appetite control and fat metab. - have made these hormones an attractive area for drug discovery programs. The potential range of strategies to target the secretion of these hormones therapeutically has been limited by an incomplete understanding of the mechanisms underlying their release. The use of organ and whole-animal perfusion techniques, cell line models and primary L- and K-cells has led to the identification of a variety of pathways involved in the sensing of carbohydrate, fat and protein in the gut lumen. This review focuses on our current understanding of these signalling mechanisms that might underlie nutrient responsiveness of L- and K-cells.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXksVKjur8%253D&md5=58cfe9b32aacd7e0d3ab64cfbbeba1df

     
223. 223

     Holst, J. J.; Deacon, C. F. Is There a Place for Incretin Therapies in Obesity and Prediabetes?. Trends Endocrinol. Metab. 2013, 24, 145– 152,  DOI: 10.1016/j.tem.2013.01.004

     [Crossref], [PubMed], [CAS], Google Scholar

     223

     Is there a place for incretin therapies in obesity and prediabetes?

     Holst, Jens Juul; Deacon, Carolyn F.

     Trends in Endocrinology and Metabolism (2013), 24 (3), 145-152CODEN: TENME4; ISSN:1043-2760. (Elsevier Ltd.)

     A review. Incretin-based therapies exploit the insulinotropic actions of the gut hormones gastric inhibitory peptide (GIP) and glucagon-like peptide-1 (GLP-1) for the treatment of diabetes and include GLP-1 receptor agonists and inhibitors of dipeptidyl peptidase-4 (DPP-4), the enzyme that inactivates the incretin hormones in the body. Both drug classes improve metabolic control in type 2 diabetes (T2DM), with GLP-1 receptor agonists also lowering body wt. Pharmacotherapy using DPP-4 inhibitors has few side effects and is wt. neutral. Animal studies support their use in prediabetes; however, human data are scarce. GLP-1 receptor agonist effects are also apparent in non-diabetic obese individuals. Therefore, incretin-based therapies, if safe, may be effective in preventing progression of prediabetes; and GLP-1 receptor agonists may have potential for use in the treatment of obesity.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXisVyitb8%253D&md5=9e95cf43ce9fff3639da6a70751011c9

     
224. 224

     Graaf, C.; Donnelly, D.; Wootten, D.; Lau, J.; Sexton, P. M.; Miller, L. J.; Ahn, J. M.; Liao, J.; Fletcher, M. M.; Yang, D.; Brown, A. J.; Zhou, C.; Deng, J.; Wang, M. W. Glucagon-Like Peptide-1 and Its Class B G Protein-Coupled Receptors: A Long March to Therapeutic Successes. Pharmacol. Rev. 2016, 68, 954– 1013,  DOI: 10.1124/pr.115.011395

     [Crossref], [PubMed], [CAS], Google Scholar

     224

     Glucagon-Like Peptide-1 and Its Class B G Protein-Coupled Receptors: A Long March to Therapeutic Successes

     Graaf Chris de; Donnelly Dan; Wootten Denise; Lau Jesper; Sexton Patrick M; Miller Laurence J; Ahn Jung-Mo; Liao Jiayu; Fletcher Madeleine M; Yang Dehua; Brown Alastair J H; Zhou Caihong; Deng Jiejie; Wang Ming-Wei

     Pharmacological reviews (2016), 68 (4), 954-1013 ISSN:.

     The glucagon-like peptide (GLP)-1 receptor (GLP-1R) is a class B G protein-coupled receptor (GPCR) that mediates the action of GLP-1, a peptide hormone secreted from three major tissues in humans, enteroendocrine L cells in the distal intestine, α cells in the pancreas, and the central nervous system, which exerts important actions useful in the management of type 2 diabetes mellitus and obesity, including glucose homeostasis and regulation of gastric motility and food intake. Peptidic analogs of GLP-1 have been successfully developed with enhanced bioavailability and pharmacological activity. Physiologic and biochemical studies with truncated, chimeric, and mutated peptides and GLP-1R variants, together with ligand-bound crystal structures of the extracellular domain and the first three-dimensional structures of the 7-helical transmembrane domain of class B GPCRs, have provided the basis for a two-domain-binding mechanism of GLP-1 with its cognate receptor. Although efforts in discovering therapeutically viable nonpeptidic GLP-1R agonists have been hampered, small-molecule modulators offer complementary chemical tools to peptide analogs to investigate ligand-directed biased cellular signaling of GLP-1R. The integrated pharmacological and structural information of different GLP-1 analogs and homologous receptors give new insights into the molecular determinants of GLP-1R ligand selectivity and functional activity, thereby providing novel opportunities in the design and development of more efficacious agents to treat metabolic disorders.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2svhtVClsQ%253D%253D&md5=5e0c0781887803121029975411562290

     
225. 225

     Deacon, C. F.; Nauck, M. A.; Toft-Nielsen, M.; Pridal, L.; Willms, B.; Holst, J. J. Both Subcutaneously and Intravenously Administered Glucagon-Like Peptide I are Rapidly Degraded from the NH2-Terminus in Type II Diabetic Patients and in Healthy Subjects. Diabetes 1995, 44, 1126– 1131,  DOI: 10.2337/diab.44.9.1126

     [Crossref], [PubMed], [CAS], Google Scholar

     225

     Both subcutaneously and intravenously administered glucagon-like peptide I are rapidly degraded from the NH2-terminus in type II diabetic patients and in healthy subjects

     Deacon, Carolyn F.; Nauck, Michael A.; Toft-Nielsen, Maibritt; Pridal, Lone; Willms, Berend; Holst, Jens J.

     Diabetes (1995), 44 (9), 1126-31CODEN: DIAEAZ; ISSN:0012-1797. (American Diabetes Association, Inc.)

     The fate of exogenous glucagon-like peptide I (GLP-I)(7-36) amide was studied in nondiabetic and type II diabetic subjects using a combination of HPLC, specific RIAs, and a sensitive ELISA, whereby intact biol. active GLP-I and its metabolites could be detd. After GLP-I administration, the intact peptide could be measured using an N-terminally direct RIA or ELISA, while the difference in concn. between these assays and a C-terminal-specific RIA allowed detn. of N-terminally truncated metabolites. S.c. GLP-I was rapidly degraded in a time-dependent manner, forming a metabolite, which coeluted on HPLC with GLP-I(9-36) amide and had the same immunoreactive profile. Thirty minutes after s.c. GLP-I administration to diabetic patients, the metabolite accounted for 88.5% of the increase in plasma immunoreactivity detd. by the C-terminal RIA, which was higher than the levels measured in healthy subjects (78.4%). I.v. infused GLP-I was also extensively degraded, but no significant differences were seen between the 2 groups. Intact GLP-I accounted for only 19.9% of the increase in immunoreactivity measured with the C-terminal RIA in normal subjects and 25.0% of the increase in diabetic subjects, the remainder being the N-terminally truncated metabolite.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXotVGhu7c%253D&md5=f8a989897d4e40a0662d51cb89aba34f

     
226. 226

     Creutzfeldt, W. O.; Kleine, N.; Willms, B.; Orskov, C.; Holst, J. J.; Nauck, M. A. Glucagonostatic Actions and Reduction of Fasting Hyperglycemia by Exogenous Glucagon-Like Peptide I(7–36) Amide in Type I Diabetic Patients. Diabetes Care 1996, 19, 580– 586,  DOI: 10.2337/diacare.19.6.580

     [Crossref], [PubMed], [CAS], Google Scholar

     226

     Glucagonostatic actions and reduction of fasting hyperglycemia by exogenous glucagon-like peptide I(7-36) amide in type I diabetic patients

     Creutzfeldt W O; Kleine N; Willms B; Orskov C; Holst J J; Nauck M A

     Diabetes care (1996), 19 (6), 580-6 ISSN:0149-5992.

     OBJECTIVE: Glucagon-like peptide I(7-36) amide (GLP-1) is a physiological incretin hormone that, in slightly supraphysiological doses, stimulates insulin secretion, lowers glucagon concentrations, and thereby normalizes elevated fasting plasma glucose concentrations in type II diabetic patients. It is not known whether GLP-1 has effects also in fasting type I diabetic patients. RESEARCH DESIGN AND METHODS: In 11 type I diabetic patients (HbA1c 9.1 +/- 2.1%; normal, 4.2-6.3%), fasting hyperglycemia was provoked by halving their usual evening NPH insulin dose. In random order on two occasions, 1.2 pmol . kg-1 . min-1 GLP-1 or placebo was infused intravenously in the morning (plasma glucose 13.7 +/- 0.9 mmol/l; plasma insulin 26 +/- 4 pmol/l). Glucose (glucose oxidase method), insulin, C-peptide, glucagon, GLP-1, cortisol, growth hormone (immunoassays), triglycerides, cholesterol, and nonesterified fatty acids (enzymatic tests) were measured. RESULTS: Glucagon was reduced from approximately 8 to 4 pmol/l, and plasma glucose was lowered from 13.4 +/- 1.0 to 10.0 +/- 1.2 mmol/l with GLP-1 administration (plasma concentrations approximately 100 pmol, P < 0.0001), but not with placebo (14.2 +/- 0.7 to 13.2 +/- 1.0). Transiently, C-peptide was stimulated from basal 0.09 +/- 0.02 to 0.19 +/- 0.06 nmol/l by GLP-1 (P < 0.0001), but not by placebo (0.07 +/- 0.02 to 0.07 +/- 0.02). There was no significant effect on nonesterified fatty acids (P = 0.34), triglycerides (P = 0.57), cholesterol (P = 0.64), cortisol (P = 0.40), or growth hormone (P = 0.53). CONCLUSIONS: Therefore, exogenous GLP-1 is able to lower fasting glycemia also in type I diabetic patients, mainly by reducing glucagon concentrations. However, this alone is not sufficient to normalize fasting plasma glucose concentrations, as was previously observed in type II diabetic patients, in whom insulin secretion (C-peptide response) was stimulated 20-fold.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK28zkvVyisg%253D%253D&md5=4e9778afeb9da7790b6b71bd60202335

     
227. 227

     Willms, B.; Werner, J.; Holst, J. J.; Orskov, C.; Creutzfeldt, W.; Nauck, M. A. Gastric Emptying, Glucose Responses, and Insulin Secretion after a Liquid Test Meal: Effects of Exogenous Glucagon-Like Peptide-1 (GLP-1)-(7–36) Amide in Type 2 (Noninsulin-Dependent) Diabetic Patients. J. Clin. Endocrinol. Metab. 1996, 81, 327– 332,  DOI: 10.1210/jcem.81.1.8550773

     [Crossref], [PubMed], [CAS], Google Scholar

     227

     Gastric emptying, glucose responses, and insulin secretion after a liquid test meal: effects of exogenous glucagon-like peptide-1 (GLP-1)-(7-36) amide in type 2 (noninsulin-dependent) diabetic patients

     Willms, Berend; Werner, Jens; Holst, Jens Juul; Oerskov, Cathrine; Creutzfeldt, Werner; Nauck, Michael A.

     Journal of Clinical Endocrinology and Metabolism (1996), 81 (1), 327-32CODEN: JCEMAZ; ISSN:0021-972X. (Endocrine Society)

     The aim of the study was to investigate whether inhibition of gastric emptying of meals plays a role in the mechanism of the blood glucose-lowering action of glucagon-like peptide-1-(7-36) amide [GLP-1-(7-36) amide] in type 2 diabetes. Eight poorly controlled type 2 diabetic patients (age, 58 ± 6 yr; body mass index, 30.0 ± 5.2 kg/m2; Hb A1c, 10.5 ± 1.2%) were studied in the fasting state (plasma glucose, 11.1 ± 1.1 mmol/L). A liq. meal of 400 mL contg. 8% amino acids and 50 g sucrose (327 kcal) was administered at time zero by a nasogastric tube. Gastric vol. was detd. by a dye diln. technique using phenol red. In randomized order, GLP-1-(7-36) amide (1.2 pmol/kg·min; Saxon Biochems.) or placebo (0.9% NaCl with 1% human serum albumin) was infused between -30 and 240 min. In the control expt., gastric emptying was completed within 120 min, and plasma glucose, insulin, C-peptide, GLP-1-(7-36) amide, and glucagon concns. transiently increased. With exogenous GLP-1-(7-36) amide (plasma level, ∼70 pmol/L), gastric vol. remained const. over the period it was measured (120 min; P < 0.0001 vs. placebo), and plasma glucose fell to normal fasting values (5.4 ± 0.7 nmol/L) within 3-4 h, whereas insulin was stimulated in most, but not all, patients, and glucagon remained at the basal level or was slightly suppressed. In conclusion, GLP-1-(7-36) amide inhibits gastric emptying in type 2 diabetic patients. Together with the stimulation of insulin and the inhibition of glucagon secretion, this effect probably contributes to the blood glucose-lowering action of GLP-1-(7-36) amide in type 2-diabetic patients when studied after meal ingestion. At the degree obsd., inhibition of gastric emptying, however, must be overcome by tachyphylaxis, redn. in dose, or pharmacol. interventions so as not to interfere with the therapeutic use of GLP-1-(7-36) amide in type 2 diabetic patients.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XkvV2jsA%253D%253D&md5=b5b0092f0773cea5dd5664b503656ece

     
228. 228

     Flint, A.; Raben, A.; Astrup, A.; Holst, J. J. Glucagon-Like Peptide 1 Promotes Satiety and Suppresses Energy Intake in Humans. J. Clin. Invest. 1998, 101, 515– 520,  DOI: 10.1172/JCI990

     [Crossref], [PubMed], [CAS], Google Scholar

     228

     Glucagon-like peptide 1 promotes satiety and suppresses energy intake in humans

     Flint, Anne; Raben, Anne; Astrup, Arne; Holst, Jens J.

     Journal of Clinical Investigation (1998), 101 (3), 515-520CODEN: JCINAO; ISSN:0021-9738. (Rockefeller University Press)

     The authors examd. the effect of i.v. infused glucagon-like peptide 1 (GLP-1) on subjective appetite sensations after an energy-fixed breakfast, and on spontaneous energy intake at an ad libitum lunch. 20 Young, healthy, normal-wt. men participated in a placebo-controlled, randomized, blinded, crossover study. Infusion (GLP-1, 50 pmol/kg/h or saline) was started simultaneously with initiation of the test meals. Visual analog scales were used to assess appetite sensations throughout the expt. and the palatability of the test meals. Blood was sampled throughout the day for anal. of plasma hormone and substrate levels. After the energy-fixed breakfast, GLP-1 infusion enhanced satiety and fullness compared with placebo. Furthermore, spontaneous energy intake at the ad libitum lunch was reduced by 12% by GLP-1 infusion compared with saline. Plasma GLP-1, insulin, glucagon, and blood glucose profiles were affected significantly by the treatment. In conclusion, the results show that GLP-1 enhanced satiety and reduced energy intake and thus may play a physiol. regulatory role in controlling appetite and energy intake in humans.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXosVagsg%253D%253D&md5=6d118aaa3ce826c6bf20a13a1cb5f381

     
229. 229

     Cheang, J. Y.; Moyle, P. M. Glucagon-Like Peptide-1 (GLP-1)-Based Therapeutics: Current Status and Future Opportunities beyond Type 2 Diabetes. ChemMedChem 2018, 13, 662– 671,  DOI: 10.1002/cmdc.201700781

     [Crossref], [PubMed], [CAS], Google Scholar

     229

     Glucagon-Like Peptide-1 (GLP-1)-Based Therapeutics: Current Status and Future Opportunities beyond Type 2 Diabetes

     Cheang, Jia Ying; Moyle, Peter M.

     ChemMedChem (2018), 13 (7), 662-671CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)

     A review. Glucagon-like peptide-1 (GLP-1) is secreted by intestinal L-cells following food intake, and plays an important role in glucose homeostasis due to its stimulation of glucose-dependent insulin secretion. Further, GLP-1 is also assocd. with protective effects on pancreatic β-cells and the cardiovascular system, decreased appetite, and wt. loss, making GLP-1 derivs. an exciting treatment for type 2 diabetes and obesity. Despite these benefits, wild-type GLP-1 exhibits a short circulation time due to its poor metabolic stability and rapid renal clearance, and must be administered by injection, making it a poor therapeutic agent. Many strategies have been used to improve the circulation time of GLP-1 (e.g., mutations, unnatural amino acids, depot formulations, use of exendin-4 sequences, and fusions with high-mol.-wt. proteins or polymers), with its therapeutic utility further improved by adding agonist activity for gastric inhibitory peptide and glucagon receptors. This minireview focuses on strategies that have been used to improve the pharmacokinetics of GLP-1 and provides an overview of GLP-1-based therapeutics in the pipeline.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXjtlyru7Y%253D&md5=49797a8747d2786a8563f28d347184ee

     
230. 230

     Baptist, G. Glucagon-Like Peptide-1 Receptor Agonists. In Handbook of Incretin-based Therapies in Type 2 Diabetes; Gough, S., Ed.; Springer: Switzerland, 2016; pp 31– 43.

     Google Scholar

     There is no corresponding record for this reference.

     
231. 231

     Dhir, G.; Cusi, K. Glucagon Like Peptide-1 Receptor Agonists for the Management of Obesity and Non-Alcoholic Fatty Liver Disease: A Novel Therapeutic Option. J. Invest. Med. 2018, 66, 7– 10,  DOI: 10.1136/jim-2017-000554

     [Crossref], [PubMed], [CAS], Google Scholar

     231

     Glucagon like peptide-1 receptor agonists for the management of obesity and non-alcoholic fatty liver disease: a novel therapeutic option

     Dhir Gauri; Cusi Kenneth; Dhir Gauri; Cusi Kenneth

     Journal of investigative medicine : the official publication of the American Federation for Clinical Research (2018), 66 (1), 7-10 ISSN:.

     Obesity is a major risk factor for the development of type 2 diabetes mellitus (T2DM), and is associated with a cluster of metabolic factors that lead to poor cardiovascular outcomes. In non-alcoholic fatty liver disease (NAFLD), liver fat (triglyceride) accumulation closely mirrors adipose tissue dysfunction and insulin resistance in obesity and T2DM. It is now recognized as the most common chronic liver disease in Westernized societies, often progressing to more severe forms of the disease such as nonalcoholic steatohepatitis (NASH), or cirrhosis and hepatocellular carcinoma. However, NAFLD remains largely overlooked by healthcare providers although it affects about two-thirds of patients with obesity and it promotes the development of T2DM. NAFLD mirrors adipose tissue and systemic insulin resistance, the liver being a 'barometer' of metabolic health. Although pioglitazone is emerging as the treatment of choice for NASH in patients with insulin-resistance, or those with T2DM, many other options are being tested. Due to their overall safety and efficacy, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are becoming one of the cornerstones for the management of both obesity and T2DM, and a novel alternative for the treatment of NAFLD. In this review, we will briefly summarize the status of GLP-1RA for the treatment of obesity and NAFLD.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1cbptlGmsQ%253D%253D&md5=bf62f1d3e88a5f4709e96b833e3c74bd

     
232. 232

     Furman, B. L. The Development of Byetta (exenatide) from the Venom of the Gila Monster as an Anti-Diabetic Agent. Toxicon 2012, 59, 464– 471,  DOI: 10.1016/j.toxicon.2010.12.016

     [Crossref], [PubMed], [CAS], Google Scholar

     232

     The development of Byetta (exenatide) from the venom of the Gila monster as an anti-diabetic agent

     Furman, Brian L.

     Toxicon (2012), 59 (4), 464-471CODEN: TOXIA6; ISSN:0041-0101. (Elsevier Ltd.)

     A review. The development of Byetta (synthetic exendin-4; exenatide) as a treatment of diabetes arose from two, parallel lines of investigation. The development of the incretin concept' which hypothesised that hormones from the gut contributed to the insulin secretion in response to meals, led to the identification of glucagon-like peptide 1 (GLP-1) as an important incretin' hormone. GLP-1 not only increases insulin secretion but increases β-cell proliferation and survival, suppresses glucagon secretion, delays gastric emptying and suppresses appetite, all of these actions contributing to a potential anti-diabetic effect. However, GLP-1 has a very short half due to its rapid breakdown by dipeptidyl peptidase IV and ectopeptidases. A systematic investigation of the compn. and activity of venom from the Gila monster, Heloderma suspectum, led to the isolation of a 39-amino acid peptide, designated exendin-4, showing 53% structural homol. with GLP-1(7-36). Exendin-4 mimicked GLP-1 through stimulating the GLP-1 receptor. The much greater stability of exendin-4 led to its exptl. and clin. evaluation as an anti-diabetic agent and its introduction to the market in 2005.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XisVGltbY%253D&md5=b2cf8ba0322b5eca9720c06a74b9e279

     
233. 233

     Suzuki, S.; Kawai, K.; Ohashi, S.; Mukai, H.; Yamashita, K. Comparison of the Effects of Various C-Terminal and N-Terminal Fragment Peptides of Glucagon-Like Peptide-1 on Insulin and Glucagon Release from the Isolated Perfused Rat Pancreas. Endocrinology 1989, 125, 3109– 3114,  DOI: 10.1210/endo-125-6-3109

     [Crossref], [PubMed], [CAS], Google Scholar

     233

     Comparison of the effects of various C-terminal and N-terminal fragment peptides of glucagon-like peptide-1 on insulin and glucagon release from the isolated perfused rat pancreas

     Suzuki, Seiji; Kawai, Koichi; Ohashi, Shinichi; Mukai, Hidehito; Yamashita, Kamejiro

     Endocrinology (1989), 125 (6), 3109-14CODEN: ENDOAO; ISSN:0013-7227.

     Truncated glucagon-like peptide-1 (GLP-1) possesses a potent stimulatory activity for insulin secretion and a slight inhibiting activity for glucagon secretion. The activities of N- and C-terminal fragments of GLP-1 were examd. using a rat pancreas perfusion system. Concerning the N-terminal portion, GLP-1(7-37) amide elicited a clear insulinotropic activity at 0.1 or 1 nM with the perfusate contg. 5.5 mM glucose and 5 mM arginine, while 10 nM GLP-1-(1-37) amide, -(6-37) amide, and -(8-37) amide did not. Concerning the C-terminal portion, GLP-1-(7-37) amide, -(7-37), and -(7-36) amide had a similar potency of insulinotropic activity, and GLP-1-(7-35) was less potent; 0.1 nM GLP-1-(7-35) did not stimulate insulin release, nor did 10 nM GLP-1-(7-20). Glucagon release was suppressed by 1 and 10 nM GLP-1-(7-37) amide, 10 nM GLP-1-(7-37), and 1 nM GLP-1-(7-36) amide. Other fragment peptides of GLP-1, including GLP-1-(7-35), had no effect. Apparently, histidine at position 7 of GLP-1 as a free N-terminal amino acid is very important in GLP-1's insulinotropic activity and probably in glucagon-inhibiting activity, and C-terminal amidation and the 3 C-terminal amino acids are less important for these activities.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3cXptF2itg%253D%253D&md5=b0e402b7a4e5c001f51bb44803af9427

     
234. 234

     Thum, A.; Hupe-Sodmann, K.; Goke, R.; Voigt, K.; Goke, B.; McGregor, G. P. Endoproteolysis by Isolated Membrane Peptidases Reveal Metabolic Stability of Glucagon-Like Peptide-1 Analogs, Exendins-3 and −4. Exp. Clin. Endocrinol. Diabetes 2002, 110, 113– 118,  DOI: 10.1055/s-2002-29087

     [Crossref], [PubMed], [CAS], Google Scholar

     234

     Endoproteolysis by isolated membrane peptidases reveal metabolic stability of glucagon-like peptide-1 analogs, exendins-3 and -4

     Thum, A.; Hupe-Sodmann, K.; Goke, R.; Voigt, K.; Goke, B.; McGregor, G. P.

     Experimental and Clinical Endocrinology & Diabetes (2002), 110 (3), 113-118CODEN: ECEDFQ; ISSN:0947-7349. (Johann Ambrosius Barth)

     These in vitro studies aimed to characterize the pattern and the kinetics of endoproteolysis of the insulinotropic hormone glucagon-like peptide-1 (GLP-1) and related peptides by native ectopeptidases. Peptides were incubated with isolated rat or pig kidney brush-border microvilli membranes, which are a rich source of the ectopeptidases that are responsible for the post-secretory metab. of peptide hormones. The proteolytic products were sepd. by reversed-phase HPLC column chromatog. and characterized by mol. mass and primary structure. The relative importance of specific peptidases was established by measuring the effects of specific peptidase inhibitors on the kinetics of proteolysis. Dipeptidyl-peptidase-IV was found to be rate-limiting in the endoproteolysis of GLP-1. GLP-1 homologs, exendins-3 and -4, exhibited exceptional stability in the presence of isolated kidney microvilli membranes. Our finding that exendin-4 is several orders of magnitude more stable than GLP-1 and Ser-8-GLP-1 is esp. noteworthy given this peptide's widely reported insulinotropic potency.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38Xjs1WmsL4%253D&md5=8ff145f53d87c8a82dd511a2720285d3

     
235. 235

     Kenny, P. R.; Brady, D. E.; Torres, D. M.; Ragozzino, L.; Chalasani, N.; Harrison, S. A. Exenatide in the Treatment of Diabetic Patients with Non-Alcoholic Steatohepatitis: A Case Series. Am. J. Gastroenterol. 2010, 105, 2707– 2709,  DOI: 10.1038/ajg.2010.363

     [Crossref], [PubMed], [CAS], Google Scholar

     235

     Exenatide in the treatment of diabetic patients with non-alcoholic steatohepatitis: a case series

     Kenny Patrick R; Brady Daniel E; Torres Dawn M; Ragozzino Linda; Chalasani Naga; Harrison Stephen A

     The American journal of gastroenterology (2010), 105 (12), 2707-9 ISSN:.

     There is no expanded citation for this reference.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3M%252FhvFWgtA%253D%253D&md5=d7bb8d601873b0d2e87bdd4c75165250

     
236. 236

     Fan, H.; Pan, Q.; Xu, Y.; Yang, X. Exenatide Improves Type 2 Diabetes Concomitant with Non-Alcoholic Fatty Liver Disease. Arq. Bras. Endocrinol. Metabol. 2013, 57, 702– 708,  DOI: 10.1590/S0004-27302013000900005

     [Crossref], [PubMed], [CAS], Google Scholar

     236

     Exenatide improves type 2 diabetes concomitant with non-alcoholic fatty liver disease

     Fan Hui; Pan QingRong; Xu Yuan; Yang XinChun

     Arquivos brasileiros de endocrinologia e metabologia (2013), 57 (9), 702-8 ISSN:.

     OBJECTIVE: To investigate the effects of exenatide on blood glucose, body weight and hepatic enzymes in patients with type 2 diabetes mellitus (T2DM) and concomitant non-alcoholic fatty liver disease (NAFLD). SUBJECTS AND METHODS: One hundred and seventeen patients with T2DM and NAFLD were randomly divided into exenatide group and metformin group. Patients were treated with exenatide and metformin, respectively, for 12 weeks. RESULTS: After 12 weeks of treatment, body weight, body mass index (BMI), waist-to-hip ratio, HbA1c, FPG, 2-h PPG, ALT, AST, γ-GT, and hs-CRP were significantly reduced, and the AST/ALT ratio and adiponectin were markedly increased in both groups. BMI, waist-to-hip ratio, 2-h PPG, ALT, AST, γ-GT, and hs-CRP were markedly lower, and AST/ALT ratio and adiponectin in the exenatide group were dramatically higher than in the metformin group. CONCLUSION: Compared with metformin, exenatide is better to control blood glucose, reduces body weight and improves hepatic enzymes, attenuating NAFLD in patients with T2DM concomitant with NAFLD.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2czjtlektQ%253D%253D&md5=c3b8d8fee1080e7922fa9b514116c820

     
237. 237

     Knudsen, L. B.; Nielsen, P. F.; Huusfeldt, P. O.; Johansen, N. L.; Madsen, K.; Pedersen, F. Z.; Thogersen, H.; Wilken, M.; Agerso, H. Potent Derivatives of Glucagon-Like Peptide-1 with Pharmacokinetic Properties Suitable for Once Daily Administration. J. Med. Chem. 2000, 43, 1664– 1669,  DOI: 10.1021/jm9909645

     [ACS Full Text ], [CAS], Google Scholar

     237

     Potent derivatives of glucagon-like peptide-1 with pharmacokinetic properties suitable for once daily administration

     Knudsen, Lotte B.; Nielsen, Per F.; Huusfeldt, Per O.; Johansen, Nils L.; Madsen, Kjeld; Pedersen, Freddy Z.; Thogersen, Henning; Wilken, Michael; Agerso, Henrik

     Journal of Medicinal Chemistry (2000), 43 (9), 1664-1669CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

     A series of very potent derivs. of the 30-amino acid peptide hormone glucagon-like peptide-1 (GLP-1) is described. The compds. were all derivatized with fatty acids in order to protract their action by facilitating binding to serum albumin. GLP-1 had a potency (EC50) of 55 pM for the cloned human GLP-1 receptor. Many of the compds. had similar or even higher potencies, despite quite large substituents. All compds. derivatized with fatty acids equal to or longer than 12 carbon atoms were very protracted compared to GLP-1 and thus seem suitable for once daily administration to type 2 diabetic patients. A structure-activity relationship was obtained. GLP-1 could be derivatized with linear fatty acids up to the length of 16 carbon atoms, sometimes longer, almost anywhere in the C-terminal part without considerable loss of potency. Derivatization with two fatty acid substituents led to a considerable loss of potency. A structure-activity relationship on derivatization of specific amino acids generally was obtained. It was found that the longer the fatty acid, the more potency was lost. Simultaneous modification of the N-terminus (in order to obtain better metabolic stability) interfered with fatty acid derivatization and led to loss of potency.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXisVKksLg%253D&md5=d050c27dd6aea795191798254e2bf080

     
238. 238

     Armstrong, M. J.; Gaunt, P.; Aithal, G. P.; Barton, D.; Hull, D.; Parker, R.; Hazlehurst, J. M.; Guo, K.; LEAN trial team; Abouda, G.; Aldersley, M. A.; Stocken, D.; Gough, S. C.; Tomlinson, J. W.; Brown, R. M.; Hubscher, S. G.; Newsome, P. N. Liraglutide Safety and Efficacy in Patients with Non-Alcoholic Steatohepatitis (LEAN): a Multicentre, Double-Blind, Randomised, Placebo-Controlled Phase 2 Study. Lancet 2016, 387, 679– 690,  DOI: 10.1016/S0140-6736(15)00803-X

     [Crossref], [PubMed], [CAS], Google Scholar

     238

     Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study

     Armstrong, Matthew James; Gaunt, Piers; Aithal, Guruprasad P.; Barton, Darren; Hull, Diana; Parker, Richard; Hazlehurst, Jonathan M.; Guo, Kathy; Abouda, George; Aldersley, Mark A.; Stocken, Deborah; Gough, Stephen C.; Tomlinson, Jeremy W.; Brown, Rachel M.; Hubscher, Stefan G.; Newsome, Philip N.

     Lancet (2016), 387 (10019), 679-690CODEN: LANCAO; ISSN:0140-6736. (Elsevier Ltd.)

     Glucagon-like peptide-1 (GLP-1) analogs reduce hepatic steatosis, concns. of liver enzymes, and insulin resistance in murine models of fatty liver disease. These analogs are licensed for type 2 diabetes, but their efficacy in patients with non-alc. steatohepatitis is unknown. We assessed the safety and efficacy of the long-acting GLP-1 analog, liraglutide, in patients with non-alc. steatohepatitis. This multicenter, double-blinded, randomized, placebo-controlled phase 2 trial was conducted in four UK medical centers to assess s.c. injections of liraglutide (1·8 mg daily) compared with placebo for patients who are overweight and show clin. evidence of non-alc. steatohepatitis. Patients were randomly assigned (1:1) using a computer-generated, centrally administered procedure, stratified by trial center and diabetes status. The trial was designed using A'Hern's single-group method, which required eight (38%) of 21 successes in the liraglutide group for the effect of liraglutide to be considered clin. significant. Patients, investigators, clin. trial site staff, and pathologists were masked to treatment assignment throughout the study. The primary outcome measure was resoln. of definite non-alc. steatohepatitis with no worsening in fibrosis from baseline to end of treatment (48 wk), as assessed centrally by two independent pathologists. Anal. was done by intention-to-treat anal., which included all patients who underwent end-of-treatment biopsy. The trial was registered with ClinicalTrials.gov, no. NCT01237119. Between Aug 1, 2010, and May 31, 2013, 26 patients were randomly assigned to receive liraglutide and 26 to placebo. Nine (39%) of 23 patients who received liraglutide and underwent end-of-treatment liver biopsy had resoln. of definite non-alc. steatohepatitis compared with two (9%) of 22 such patients in the placebo group (relative risk 4·3 [95% CI 1·0-17·7]; p=0·019). Two (9%) of 23 patients in the liraglutide group vs. eight (36%) of 22 patients in the placebo group had progression of fibrosis (0·2 [0·1-1·0]; p=0·04). Most adverse events were grade 1 (mild) to grade 2 (moderate) in severity, transient, and similar in the two treatment groups for all organ classes and symptoms, with the exception of gastrointestinal disorders in 21 (81%) of 23 patients in the liraglutide group and 17 (65%) of 22 patients in the placebo group, which included diarrhea (ten [38%] patients in the liraglutide group vs five [19%] in the placebo group), constipation (seven [27%] vs none), and loss of appetite (eight [31%] vs two [8%]). Liraglutide was safe, well tolerated, and led to histol. resoln. of non-alc. steatohepatitis, warranting extensive, longer-term studies. Wellcome Trust, National Institute of Health Research, and Novo Nordisk.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhvVygsbzK&md5=db5853aead647d1df8314b74aa94ce9b

     
239. 239

     Tang, A.; Rabasa-Lhoret, R.; Castel, H.; Wartelle-Bladou, C.; Gilbert, G.; Massicotte-Tisluck, K.; Chartrand, G.; Olivie, D.; Julien, A. S.; de Guise, J.; Soulez, G.; Chiasson, J. L. Effects of Insulin Glargine and Liraglutide Therapy on Liver Fat as Measured by Magnetic Resonance in Patients with Type 2 Diabetes: A Randomized Trial. Diabetes Care 2015, 38, 1339– 1346,  DOI: 10.2337/dc14-2548

     [Crossref], [PubMed], [CAS], Google Scholar

     239

     Effects of insulin glargine and liraglutide therapy on liver fat as measured by magnetic resonance in patients with type 2 diabetes: a randomized trial

     Tang, An; Rabasa-Lhoret, Remi; Castel, Helene; Wartelle-Bladou, Claire; Gilbert, Guillaume; Massicotte-Tisluck, Karine; Chartrand, Gabriel; Olivie, Damien; Julien, Anne-Sophie; de Guise, Jacques; Soulez, Gilles; Chiasson, Jean-Louis

     Diabetes Care (2015), 38 (7), 1339-1346CODEN: DICAD2; ISSN:0149-5992. (American Diabetes Association, Inc.)

     OBJECTIVE This study detd. the effects of insulin vs. liraglutide therapy on liver fat in patients with type 2 diabetes inadequately controlled with oral agents therapy, including metformin. RESEARCH DESIGN AND METHODS Thirty-five patients with type 2 diabetes inadequately controlled on metformin monotherapy or in combination with other oral antidiabetic medications were randomized to receive insulin glargine or liraglutide therapy for 12 wk. The liver proton d. fat fraction (PDFF) was measured by MRS. The mean liver PDFF, the total liver vol., and the total liver fat index were measured by MRI. The Student t test, the Fisher exact test, and repeated-measures ANOVA were used for statistical anal. RESULTS Insulin treatment was assocd. with a significant improvement in glycated Hb (7.9% to 7.2% [62.5 to 55.2 mmol/mol], P = 0.005), a trend toward a decrease in MRS-PDFF (12.6% to 9.9%, P = 0.06), and a significant decrease in liver mean MRI-PDFF (13.8% to 10.6%, P = 0.005), liver vol. (2,010.6 to 1,858.7 mL, P = 0.01), and the total liver fat index (304.4 vs. 209.3 % · mL, P = 0.01). Liraglutide treatment was also assocd. with a significant improvement in glycated Hb (7.6% to 6.7% [59.8 to 50.2 mmol/mol], P < 0.001) but did not change MRS-PDFF (P = 0.80), liver mean MRI-PDFF (P = 0.15), liver vol. (P = 0.30), or the total liver fat index (P = 0.39). CONCLUSIONS The administration of insulin glargine therapy reduced the liver fat burden in patients with type 2 diabetes. However, the improvements in the liver fat fraction and glycemia control were not significantly different from those in the liraglutide group.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhs1WhsrvE&md5=ac52dda4f5137e599f6c0aeda2f3c76c

     
240. 240

     Feng, W.; Gao, C.; Bi, Y.; Wu, M.; Li, P.; Shen, S.; Chen, W.; Yin, T.; Zhu, D. Randomized Trial Comparing the Effects of Gliclazide, Liraglutide, and Metformin on Diabetes with Non-Alcoholic Fatty Liver Disease. J. Diabetes 2017, 9, 800– 809,  DOI: 10.1111/1753-0407.12555

     [Crossref], [PubMed], [CAS], Google Scholar

     240

     Randomized trial comparing the effects of gliclazide, liraglutide, and metformin on diabetes with non-alcoholic fatty liver disease

     Feng, Wenhuan; Gao, Caixia; Bi, Yan; Wu, Min; Li, Ping; Shen, Shanmei; Chen, Wei; Yin, Tingting; Zhu, Dalong

     Journal of Diabetes (2017), 9 (8), 800-809CODEN: JDOIAC; ISSN:1753-0407. (Wiley-Blackwell)

     Background : The aim of the present study was to compare the effects of gliclazide, liraglutide, and metformin in type 2 diabetes mellitus (T2DM) patients with non-alc. fatty liver disease (NAFLD). Methods : Eighty-seven subjects were randomized to receive liraglutide, metformin, or gliclazide for 24 wk. Primary outcomes included HbA1c levels, intrahepatic fat (IHF) content, and liver function. Results : Both HbA1c levels and IHF content were reduced after treatment in all three groups. However, HbA1c levels were lower in the liraglutide- and metformin-treated groups than in the gliclazide-treated group, and redns. in IHF content were greater with liraglutide than with gliclazide. Liraglutide and metformin treatments reduced wt. and improved liver function. Changes in IHF content were pos. correlated with redns. in serum alanine aminotransferase and triglyceride levels, as well as wt. At 24 wk, redns. in IHF content were greater in subjects with wt. loss ≥5%, changes in waistline ≤0 cm (including decreases in waistline), HbA1c redns. ≥2.5%, and HbA1c levels <6.5%. Conclusions : In T2DM patients with NAFLD, compared with liraglutide and metformin, gliclazide resulted in less improvement in liver function, redns. in IHF content and HbA1c levels, and less wt. loss; in addn., slightly better improvements were achieved with liraglutide than with metformin.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtFemt7rO&md5=07e1943061c81feb6aacd9147da9a53b

     
241. 241

     Lau, J.; Bloch, P.; Schaffer, L.; Pettersson, I.; Spetzler, J.; Kofoed, J.; Madsen, K.; Knudsen, L. B.; McGuire, J.; Steensgaard, D. B.; Strauss, H. M.; Gram, D. X.; Knudsen, S. M.; Nielsen, F. S.; Thygesen, P.; Reedtz-Runge, S.; Kruse, T. Discovery of the Once-Weekly Glucagon-Like Peptide-1 (GLP-1) Analogue Semaglutide. J. Med. Chem. 2015, 58, 7370– 7380,  DOI: 10.1021/acs.jmedchem.5b00726

     [ACS Full Text ], [CAS], Google Scholar

     241

     Discovery of the Once-Weekly Glucagon-Like Peptide-1 (GLP-1) Analogue Semaglutide

     Lau, Jesper; Bloch, Paw; Schaffer, Lauge; Pettersson, Ingrid; Spetzler, Jane; Kofoed, Jacob; Madsen, Kjeld; Knudsen, Lotte Bjerre; McGuire, James; Steensgaard, Dorte Bjerre; Strauss, Holger Martin; Gram, Dorte X.; Knudsen, Sanne Moeller; Nielsen, Flemming Seier; Thygesen, Peter; Reedtz-Runge, Steffen; Kruse, Thomas

     Journal of Medicinal Chemistry (2015), 58 (18), 7370-7380CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

     Liraglutide is an acylated glucagon-like peptide-1 (GLP-1) analog that binds to serum albumin in vivo and is approved for once-daily treatment of diabetes as well as obesity. The aim of the present studies was to design a once weekly GLP-1 analog by increasing albumin affinity and secure full stability against metabolic degrdn. The fatty acid moiety and the linking chem. to GLP-1 were the key features to secure high albumin affinity and GLP-1 receptor (GLP-1R) potency and in obtaining a prolonged exposure and action of the GLP-1 analog. Semaglutide was selected as the optimal once weekly candidate. Semaglutide has two amino acid substitutions compared to human GLP-1 (Aib8, Arg34) and is derivatized at lysine 26. The GLP-1R affinity of semaglutide (0.38 ± 0.06 nM) was three-fold decreased compared to liraglutide, whereas the albumin affinity was increased. The plasma half-life was 46.1 h in mini-pigs following i.v. administration, and semaglutide has an MRT of 63.6 h after s.c. dosing to mini-pigs. Semaglutide is currently in phase 3 clin. testing.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtl2qu7%252FM&md5=0478fe17f9f4dcc0cb58919b1c55869a

     
242. 242

     Gilead - Novo Nordisk Collaboration. https://www.gilead.com/news-and-press/press-room/press-releases/2019/4/gilead-sciences-and-novo-nordisk-announce-intent-to-initiate-a-clinical-collaboration-in-nash (accessed Sept 25, 2019).

     Google Scholar

     There is no corresponding record for this reference.

     
243. 243

     Smelcerovic, A.; Lazarevic, J.; Tomovic, K.; Anastasijevic, M.; Jukic, M.; Kocic, G.; Anderluh, M. An Overview, Advantages and Therapeutic Potential of Nonpeptide Positive Allosteric Modulators of Glucagon-Like Peptide-1 Receptor. ChemMedChem 2019, 14, 514– 521,  DOI: 10.1002/cmdc.201800699

     [Crossref], [PubMed], [CAS], Google Scholar

     243

     An Overview, Advantages and Therapeutic Potential of Nonpeptide Positive Allosteric Modulators of Glucagon-Like Peptide-1 Receptor

     Smelcerovic, Andrija; Lazarevic, Jelena; Tomovic, Katarina; Anastasijevic, Marija; Jukic, Marko; Kocic, Gordana; Anderluh, Marko

     ChemMedChem (2019), 14 (5), 514-521CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)

     A review. Due to uncomfortable injection regimens of peptidic agonists of glucagon-like peptide-1 receptor (GLP-1R), orally available nonpeptide pos. allosteric modulators (PAMs) of GLP-1Rs are foreseen as the possible future mainstream therapy for type 2 diabetes. Herein, current GLP-1R PAMs are reviewed. Based on the effectiveness and in silico predicted physicochem. properties, pharmacokinetics, and toxicity, possible candidates for further development as oral drugs were selected. The suggestion is that GLP-1R PAMs might be used orally alone or in combination with dipeptidyl peptidase-4 (DPP-4) inhibitors, which could offer an optimal treatment option next to metformin monotherapy in type 2 diabetes mellitus, or in a wider spectrum of indications. Quercetin acts as a GLP-1R PAM and DPP-4 inhibitor, and therefore, might be considered as a pioneering agent with a dual mechanism of action, in terms of GLP-1R pos. allosteric modulation and DPP-4 inhibition for potentiating GLP-1 dependent effects.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitVyqs7k%253D&md5=2b8636401cf8f6489c8c6b64e1b4911a

     
244. 244

     Mjalli, A. M. M.; Polisetti, D. R.; Yokum, T. S.; Kalpathy, S.; Guzel, M.; Behme, C.; Davis, S. T. Oxadiazoanthracene Compounds for the Treatment of Diabetes. International Patent WO2009111700, 2009.

     Google Scholar

     There is no corresponding record for this reference.

     
245. 245

     Rao, M. Ligands for the GLP-1 Receptor and Methods for Discovery Thereof. International Patent WO2009126709, 2009.

     Google Scholar

     There is no corresponding record for this reference.

     
246. 246

     Freeman, J. L. R.; Dunn, I.; Valcarce, C. Preclinical Findings with Oral GLP-1 Receptor Agonist TTP273 Reinforce Importance of Neuro-Enteroendocrine Signaling. Presented at the 76th Scientific Session of the American Diabetes Association, New Orleans, USA, June 10–14, 2016; 1177-P.

     Google Scholar

     There is no corresponding record for this reference.

     
247. 247

     Freeman, J. L. R.; Dunn, I.; Valcarce, C. Beyond Topline Results for the Oral (Non-Peptide) GLP-1R Agonist TTP273 in Type 2 Diabetes: How much and When? Presented at the European Associate for the Study of Diabetes, Lisbon, Portugal, September 11–15, 2017; Abstract 112.

     Google Scholar

     There is no corresponding record for this reference.

     
248. 248

     Freeman, J.; Soeder, T.; Dunn, I.; Valcarce, C. Is Less More? Learning to Dose the Oral, Non-peptide GLP-1R Agonist, TTP273 in Type 2 Diabetics. Presented at the 77th Scientific Session of the American Diabetes Association, San Diego, USA, June 9–13, 2017; 168-P.

     Google Scholar

     There is no corresponding record for this reference.

     
249. 249

     Freeman, J.; Dvergsten, C.; Dunn, I.; Valcarce, C. TTP273, Oral (Nonpeptide) GLP-1R Agonist: Improved Glycemic Control Without Nausea and Vomiting in Phase 2. Presented at the 77th Scientific Session of the American Diabetes Association, San Diego, USA, June 9–13, 2017; 1220-P.

     Google Scholar

     There is no corresponding record for this reference.

     
250. 250

     Yoshino, H.; Tsuchiya, S.; Matsuo, A.; Sato, T.; Nishimoto, M.; Oguri, K.; Ogawa, H.; Nishimura, Y.; Furuta, Y.; Kashiwagi, H.; Hori, N.; Kamon, T.; Shiraishi, T.; Yoshida, S.; Kawai, T.; Tanida, S.; Aoki, M. Pyrazolopyridine Derivative Having GLP-1 Receptor Agonist Effect. International Patent WO2018056453, 2018.

     Google Scholar

     There is no corresponding record for this reference.

     
251. 251

     Kawai, T.; Tanino, F.; Fukazawa, M.; Ogawa, K.; Nagao, S.; Yoshino, H.; Komatsu, S.-I.; Suzuki, Y.; Kawabe, Y. OWL833, An Orally Active Nonpeptide GLP-1 Receptor Agonist, Improves Glucose Tolerance by Increasing Insulin Secretion and Reduces Food Intake of Cynomolgus Monkeys. Presented at the 78th Scientific Session of the American Diabetes Association, Orlando, USA, June 22–26, 2018; 1118-P.

     Google Scholar

     There is no corresponding record for this reference.

     
252. 252

     Edmonds, D.; Fortin, J.-P.; Griffor, M.; Jackson, M.; Kalgutkar, A.; Kuzmiski, J.; Landis, M.; Lettiere, D.; Limberakis, C.; Liras, S.; Loria, P.; Griffith, D.; Mathiowetz, A.; Piotrowski, D.; Price, D.; Stevens, L.; Rolph, T.; Ruggeri, R.; Saxena, A.; Smith, A.; Tess, D.; Wei, L.; Bagley, S.; Buckeridge, C.; Conn, E.; Curto, J.; Derksen, D.; Eng, H.; Flanagan, M.; Discovery of PF-06882961: A Potent, Orally Bioavailable Small Molecule Agonist of The GLP-1 Receptor. In 257th American Chemical Society National Meeting & Exposition, Orlando, USA, March 31–April 4, 2019; MEDI 274.

     Google Scholar

     There is no corresponding record for this reference.

     
253. 253

     Griffith, D. A. GLP-1R Agonist. In 17th Annual Discovery on Target; Cambridge Healthtech Institute: Boston, USA, 2019.

     Google Scholar

     There is no corresponding record for this reference.

     
254. 254

     Ehrenkranz, J. R.; Lewis, N. G.; Kahn, C. R.; Roth, J. Phlorizin: A Review. Diabetes/Metab. Res. Rev. 2005, 21, 31– 38,  DOI: 10.1002/dmrr.532

     [Crossref], [PubMed], [CAS], Google Scholar

     254

     Phlorizin: a review

     Ehrenkranz, Joel R. L.; Lewis, Norman G.; Kahn, C. Ronald; Roth, Jesse

     Diabetes/Metabolism Research and Reviews (2005), 21 (1), 31-38CODEN: DMRRFM; ISSN:1520-7552. (John Wiley & Sons Ltd.)

     A review. The dihydrochalcone phlorizin is a natural product and dietary constituent found in a no. of fruit trees. It has been used as a pharmaceutical and tool for physiol. research for over 150 years. Phlorizin's principal pharmacol. action is to produce renal glycosuria and block intestinal glucose absorption through inhibition of the sodium-glucose symporters located in the proximal renal tubule and mucosa of the small intestine. This review covers the role phlorizin has played in the history of diabetes mellitus and its use as an agent to understand fundamental concepts in renal physiol. as well as summarizes the physiol. of cellular glucose transport and the pathophysiol. of renal glycosuria. It reviews the biol. and pathobiol. of glucose transporters and discusses the medical botany of phlorizin and the potential effects of plant flavonoids, such as phlorizin, on human metab. Lastly, it describes the clin. pharmacol. and toxicol. of phlorizin, including investigational uses of phlorizin and phlorizin analogs in the treatment of diabetes, obesity, and stress hyperglycemia.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhs12gs7c%253D&md5=03f04faab4da2f9ac1e5383036f98649

     
255. 255

     Mudaliar, S.; Polidori, D.; Zambrowicz, B.; Henry, R. R. Sodium-Glucose Cotransporter Inhibitors: Effects on Renal and Intestinal Glucose Transport: From Bench to Bedside. Diabetes Care 2015, 38, 2344– 2353,  DOI: 10.2337/dc15-0642

     [Crossref], [PubMed], [CAS], Google Scholar

     255

     Sodium-glucose cotransporter inhibitors: effects on renal and intestinal glucose transport

     Mudaliar, Sunder; Polidori, David; Zambrowicz, Brian; Henry, Robert R.

     Diabetes Care (2015), 38 (12), 2344-2353CODEN: DICAD2; ISSN:0149-5992. (American Diabetes Association, Inc.)

     Type 2 diabetes is a chronic disease with disabling micro- and macrovascular complications that lead to excessive morbidity and premature mortality. It affects hundreds of millions of people and imposes an undue economic burden on populations across the world. Although insulin resistance and insulin secretory defects play a major role in the pathogenesis of hyperglycemia, several other metabolic defects contribute to the initiation/worsening of the diabetic state. Prominent among these is increased renal glucose reabsorption, which is maladaptive in patients with diabetes. Instead of an increase in renal glucose excretion, which could ameliorate hyperglycemia, there is an increase in renal glucose reabsorption, which helps sustain hyperglycemia in patients with diabetes. The sodium-glucose cotransporter (SGLT) 2 inhibitors are novel antidiabetes agents that inhibit renal glucose reabsorption and promote glucosuria, thereby leading to redns. in plasma glucose concns. In this article, we review the long journey from the discovery of the glucosuric agent phlorizin in the bark of the apple tree through the animal and human studies that led to the development of the current generation of SGLT2 inhibitors.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xht1OqsLbN&md5=fb068fc034d96933e079b7879bad18a1

     
256. 256

     Wright, E. M. Renal Na⁺-Glucose Cotransporters. Am. J. Physiol. Renal Physiol. 2001, 280, F10– 18,  DOI: 10.1152/ajprenal.2001.280.1.F10

     [Crossref], [PubMed], [CAS], Google Scholar

     256

     Renal Na+-glucose cotransporters

     Wright, Ernest M.

     American Journal of Physiology (2001), 280 (1, Pt. 2), F10-F18CODEN: AJPHAP; ISSN:0002-9513. (American Physiological Society)

     A review with 75 refs. In humans, the kidneys filter ∼180 g of D-glucose from plasma each day, and this is normally reabsorbed in the proximal tubules. Although the mechanism of reabsorption is well understood, Na+-glucose cotransport across the brush-border membrane and facilitated diffusion across the basolateral membrane, questions remain about the identity of the genes responsible for cotransport across the brush border. Genetic studies suggest that 2 different genes regulate Na+-glucose cotransport, and there is evidence from animal studies to suggest that the major bulk of sugar is reabsorbed in the convoluted proximal tubule by a low-affinity, high-capacity transporter and that the remainder is absorbed in the straight proximal tubule by a high-affinity, low-capacity transporter. There are at least 3 different candidates for these human renal Na+-glucose cotransporters. This review focuses on the structure-function relations of these 3 transporters, SGLT1, SGLT2, and SGLT3.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXjtVyku7g%253D&md5=597daaeec53beb4a6a1cc58415ad4f90

     
257. 257

     Nishimura, M.; Naito, S. Tissue-Specific mRNA Expression Profiles of Human ATP-Binding Cassette and Solute Carrier Transporter Superfamilies. Drug Metab. Pharmacokinet. 2005, 20, 452– 477,  DOI: 10.2133/dmpk.20.452

     [Crossref], [PubMed], [CAS], Google Scholar

     257

     Tissue-specific mRNA expression profiles of human ATP-binding cassette and solute carrier transporter superfamilies

     Nishimura, Masuhiro; Naito, Shinsaku

     Drug Metabolism and Pharmacokinetics (2005), 20 (6), 452-477CODEN: DMPRB8; ISSN:1347-4367. (Japanese Society for the Study of Xenobiotics)

     Pairs of forward and reverse primers and TaqMan probes specific to each of 46 human ATP-binding cassette (ABC) transporters and 108 human solute carrier (SLC) transporters were prepd. The mRNA expression level of each target transporter was analyzed in total RNA from single and pooled specimens of various human tissues (adrenal gland, bone marrow, brain, colon, heart, kidney, liver, lung, pancreas, peripheral leukocytes, placenta, prostate, salivary gland, skeletal muscle, small intestine, spinal cord, spleen, stomach, testis, thymus, thyroid gland, trachea, and uterus) by real-time reverse transcription PCR using an ABI PRISM 7700 sequence detector system. In contrast to previous methods for analyzing the mRNA expression of single ABC and SLC genes such as Northern blotting, the method allowed the authors' to perform sensitive, semiautomatic, rapid, and complete anal. of ABC and SLC transporters in total RNA samples. The newly detd. expression profiles were then used to study the gene expression in 23 different human tissues, and tissues with high transcriptional activity for human ABC and SLC transporters were identified. These results are expected to be valuable for establishing drug transport-mediated screening systems for new chem. entities in new drug development and for research concerning the clin. diagnosis of disease.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XitVOmsbk%253D&md5=eaa00db131c7f3335e1cbd9e89900d04

     
258. 258

     Turk, E.; Zabel, B.; Mundlos, S.; Dyer, J.; Wright, E. M. Glucose/Galactose Malabsorption Caused by a Defect in the Na+/Glucose Cotransporter. Nature 1991, 350, 354– 356,  DOI: 10.1038/350354a0

     [Crossref], [PubMed], [CAS], Google Scholar

     258

     Glucose/galactose malabsorption caused by a defect in the sodium/glucose cotransporter

     Turk, E.; Zabel, B.; Mundlos, S.; Dyer, J.; Wright, E. M.

     Nature (London, United Kingdom) (1991), 350 (6316), 354-6CODEN: NATUAS; ISSN:0028-0836.

     Intestinal biopsies of glucose/galactose malabsorption (GGM) patients have revealed a specific defect in Na+-dependent absorption of glucose in the brush border. Normal glucose absorption is mediated by the Na+/glucose cotransporter (encoded by gene SGLT1) in the brush border membrane of the intestinal epithelium. SGLT1 CDNA and genomic DNA were amplified from members of a family affected with GGM by the polymerase chain reaction. Sequence anal. of the amplified products revealed a single missense mutation in SGLT1 which cosegregates with the GGM phenotype and results in a complete loss of Na+-dependent glucose transport in Xenopus oocytes injected with this complementary RNA.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3MXitVSru7s%253D&md5=5fab675053f5396c5b4059ef36f36d93

     
259. 259

     Martin, M. G.; Turk, E.; Lostao, M. P.; Kerner, C.; Wright, E. M. Defects in Na+/Glucose Cotransporter (SGLT1) Trafficking and Function Cause Glucose-Galactose Malabsorption. Nat. Genet. 1996, 12, 216– 220,  DOI: 10.1038/ng0296-216

     [Crossref], [PubMed], [CAS], Google Scholar

     259

     Defects in Na+/glucose cotransporter (SGLT1) trafficking and function cause glucose-galactose malabsorption

     Martin, Martin C.; Turk, Eric; Lostao, M. Pilar; Kerner, Cynthia; Wright, Ernest M.

     Nature Genetics (1996), 12 (2), 216-20CODEN: NGENEC; ISSN:1061-4036. (Nature Publishing Co.)

     Cotransporters harness ion gradients to drive 'active' transport of substrates into cells, for example, the Na+/glucose cotransporter (SGLT1) couples sugar transport to Na+ gradients across the intestinal brush border. Glucose-Galactose Malabsorption (GGM) is caused by a defect in SGLT1. The phenotype is neonatal onset of diarrhea that results in death unless these sugars are removed from the diet. Previously the authors showed that two sisters with GGM had a missense mutation in the SGLT1 gene. The gene has now been screened in 30 new patients, and a heterologous expression system has been used to link the mutations to the phenotype.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XosFCltw%253D%253D&md5=97e4435b2becc139cc05514e96b6f5e4

     
260. 260

     van den Heuvel, L. P.; Assink, K.; Willemsen, M.; Monnens, L. Autosomal Recessive Renal Glucosuria Attributable to a Mutation in the Sodium Glucose Cotransporter (SGLT2). Hum. Genet. 2002, 111, 544– 547,  DOI: 10.1007/s00439-002-0820-5

     [Crossref], [PubMed], [CAS], Google Scholar

     260

     Autosomal recessive renal glucosuria attributable to a mutation in the sodium glucose cotransporter (SGLT2)

     van den Heuvel, L. P.; Assink, K.; Willemsen, M.; Monnens, L.

     Human Genetics (2002), 111 (6), 544-547CODEN: HUGEDQ; ISSN:0340-6717. (Springer-Verlag)

     Patients with primary renal glucosuria have normal blood glucose levels, normal oral glucose tolerance test results, and isolated persistent glucosuria. Congenital renal glucosuria is postulated to be attributable to defects in the SGLT2 gene. The Na+/glucose cotransporter gene SGLT2 (=SLC5A2) was analyzed in a Turkish patient with congenital isolated renal glucosuria. Genomic DNA was used as a template for amplification by the polymerase chain reaction of each of the 14 exons of the SGLT2 gene. The amplification products were sequenced. DNA sequence anal. revealed a homozygous nonsense mutation in exon 11 of the SGLT2 gene leading to the formation of a truncated cotransporter. Both parents and a younger brother, all three without renal glucosuria, are heterozygous for the nonsense mutation. The data provide the first direct evidence of an etiol. role for the sodium/glucose cotransporter type 2 in the pathogenesis of renal glucosuria.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXhvFCis7k%253D&md5=db038172aa6c76b98ce19915514e2203

     
261. 261

     Santer, R.; Calado, J. Familial Renal Glucosuria and SGLT2: From a Mendelian Trait to a Therapeutic Target. Clin. J. Am. Soc. Nephrol. 2010, 5, 133– 141,  DOI: 10.2215/CJN.04010609

     [Crossref], [PubMed], [CAS], Google Scholar

     261

     Familial renal glucosuria and SGLT2: from a Mendelian trait to a therapeutic target

     Santer, Rene; Calado, Joaquim

     Clinical Journal of the American Society of Nephrology (2010), 5 (1), 133-141CODEN: CJASC7; ISSN:1555-9041. (American Society of Nephrology)

     A review. Four members of two glucose transporter families, SGLT1, SGLT2, GLUT1, and GLUT2, are differentially expressed in the kidney, and three of them have been shown to be necessary for normal glucose resorption from the glomerular filtrate. Mutations in SGLT1 are assocd. with glucose-galactose malabsorption, SGLT2 with familial renal glucosuria (FRG), and GLUT2 with Fanconi-Bickel syndrome. Patients with FRG have decreased renal tubular resorption of glucose from the urine in the absence of hyperglycemia and any other signs of tubular dysfunction. Glucosuria in these patients can range from <1 to >150 g/1.73 m2 per d. The majority of patients do not seem to develop significant clin. problems over time, and further description of specific disease sequelae in these individuals is reviewed. SGLT2, a crit. transporter in tubular glucose resorption, is located in the S1 segment of the proximal tubule, and, as such, recent attention has been given to SGLT2 inhibitors and their utility in patients with type 2 diabetes, who might benefit from the glucose-lowering effect of such compds. A natural analogy is made of SGLT2 inhibition to observations with inactivating mutations of SGLT2 in patients with FRG, the hereditary condition that results in benign glucosuria. This review provides an overview of renal glucose transport physiol., FRG and its clin. course, and the potential of SGLT2 inhibition as a therapeutic target in type 2 diabetes.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXitVKksLY%253D&md5=17ecc36146ccd177cfccbcedfa1012de

     
262. 262

     Lam, J. T.; Martin, M. G.; Turk, E.; Hirayama, B. A.; Bosshard, N. U.; Steinmann, B.; Wright, E. M. Missense Mutations in SGLT1 Cause Glucose-Galactose Malabsorption by Trafficking Defects. Biochim. Biophys. Acta, Mol. Basis Dis. 1999, 1453, 297– 303,  DOI: 10.1016/S0925-4439(98)00109-4

     [Crossref], [PubMed], [CAS], Google Scholar

     262

     Missense mutations in SGLT1 cause glucose-galactose malabsorption by trafficking defects

     Lam, Jason T.; Martin, Martin G.; Turk, Eric; Hirayama, Bruce A.; Bosshard, Nils U.; Steinmann, Beat; Wright, Ernest M.

     Biochimica et Biophysica Acta, Molecular Basis of Disease (1999), 1453 (2), 297-303CODEN: BBADEX; ISSN:0925-4439. (Elsevier B.V.)

     Glucose-galactose malabsorption (GGM) is an autosomal recessive disorder caused by defects in the Na+/glucose cotransporter (SGLT1). Neonates present with severe diarrhea while on any diet contg. glucose and/or galactose. This study focuses on a patient of Swiss and Dominican descent. All 15 exons of SGLT1 were screened using single stranded conformational polymorphism analyses, and aberrant PCR products were sequenced. Two missense mutations, Gly318Arg and Ala468Val, were identified. SGLT1 mutants were expressed in Xenopus laevis oocytes for radiotracer uptake, electrophysiol. expts., and Western blotting. Uptakes of [14C]α-methyl-d-glucoside by the mutants were 5% or less than that of wild-type. Two-electrode voltage-clamp expts. confirmed the transport defects, as no noticeable sugar-induced current could be elicited from either mutant. Western blots of cell protein showed levels of each SGLT1 mutant protein comparable to that of wild-type, and that both were core-glycosylated. Presteady-state current measurements indicated an absence of SGLT1 in the plasma membrane. The authors suggest that the compd. heterozygote missense mutations G318R and A468V lead to GGM in this patient by defective trafficking of mutant proteins from the endoplasmic reticulum to the plasma membrane.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXhsVWnsr4%253D&md5=fed31438eb40598f09e6ca33a44778f3

     
263. 263

     Danne, T.; Biester, T.; Kordonouri, O. Combined SGLT1 and SGLT2 Inhibitors and Their Role in Diabetes Care. Diabetes Technol. Ther. 2018, 20, S269– S277,  DOI: 10.1089/dia.2018.0081

     [Crossref], [PubMed], Google Scholar

     There is no corresponding record for this reference.

     
264. 264

     Hsia, D. S.; Grove, O.; Cefalu, W. T. An Update on Sodium-Glucose Co-Transporter-2 Inhibitors for the Treatment of Diabetes Mellitus. Curr. Opin. Endocrinol., Diabetes Obes. 2016, 24, 73– 79,  DOI: 10.1097/MED.0000000000000311

     [Crossref], Google Scholar

     There is no corresponding record for this reference.

     
265. 265

     Zhang, Y.; Ban, H.; Yu, R.; Wang, Z.; Zhang, D. Recent Progress of Sodium-Glucose Transporter 2 Inhibitors as Potential Antidiabetic Agents. Future Med. Chem. 2018, 10, 1261– 1276,  DOI: 10.4155/fmc-2017-0241

     [Crossref], [PubMed], [CAS], Google Scholar

     265

     Recent progress of sodium-glucose transporter 2 inhibitors as potential antidiabetic agents

     Zhang, Yajing; Ban, Huazhuo; Yu, Runan; Wang, Zhijian; Zhang, Dayong

     Future Medicinal Chemistry (2018), 10 (10), 1261-1276CODEN: FMCUA7; ISSN:1756-8919. (Future Science Ltd.)

     A review. SGLT2 inhibitors were promising and novel antidiabetic drugs which suppressed glucose reabsorption and increased urinary glucose exertion. This review paper are aimed to summarize the recent progress of SGLT2 inhibitors during the last 5 years. This paper first summarizes the information of SGLT2 inhibitors, including mechanism, evolution and then focuses on the recent efforts on structure-activity relationships and structural optimization of SGLT2 inhibitors. Finally, the corresponding clin. therapeutic efficacy and adverse drug reaction in patients with Type 2 diabetes are discussed in detail.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtVajsL3L&md5=5e7d9c018fa0a27cd60ea980544e086b

     
266. 266

     Kalra, S. Sodium Glucose Co-Transporter-2 (SGLT2) Inhibitors: A Review of their Basic and Clinical Pharmacology. Diabetes Ther. 2014, 5, 355– 366,  DOI: 10.1007/s13300-014-0089-4

     [Crossref], [PubMed], [CAS], Google Scholar

     266

     Sodium Glucose Co-Transporter-2 (SGLT2) Inhibitors: A Review of Their Basic and Clinical Pharmacology

     Kalra, Sanjay

     Diabetes Therapy (2014), 5 (2), 355-366CODEN: DTIHAP; ISSN:1869-6961. (Springer Healthcare Ltd.)

     A review. Sodium-glucose co-transporter-2 (SGLT2) inhibitors are a newly developed class of oral anti-diabetic drugs (OADs) with a unique mechanism of action. This review describes the biochem. and physiol. underlying the use of SGLT2 inhibitors, and their clin. pharmacol., including mechanism of action and posol. The pragmatic placement of these mols. in the existing OAD arena is also discussed.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXitVCgt7jI&md5=e3aa0a1431f783accef94b17fd8108e8

     
267. 267

     Tsujihara, K.; Hongu, M.; Saito, K.; Kawanishi, H.; Kuriyama, K.; Matsumoto, M.; Oku, A.; Ueta, K.; Tsuda, M.; Saito, A. Na(+)-Glucose Cotransporter (SGLT) Inhibitors as Antidiabetic Agents. 4. Synthesis and Pharmacological Properties of 4’-Dehydroxyphlorizin Derivatives Substituted on the B Ring. J. Med. Chem. 1999, 42, 5311– 5324,  DOI: 10.1021/jm990175n

     [ACS Full Text ], [CAS], Google Scholar

     267

     Na+-Glucose Cotransporter (SGLT) Inhibitors as Antidiabetic Agents. 4. Synthesis and Pharmacological Properties of 4'-Dehydroxyphlorizin Derivatives Substituted on the B Ring

     Tsujihara, Kenji; Hongu, Mitsuya; Saito, Kunio; Kawanishi, Hiroyuki; Kuriyama, Kayoko; Matsumoto, Mamoru; Oku, Akira; Ueta, Kiichiro; Tsuda, Minoru; Saito, Akira

     Journal of Medicinal Chemistry (1999), 42 (26), 5311-5324CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

     In the authors' studies of Na+-glucose cotransporter (SGLT) inhibitors as antidiabetic agents, a series of novel 4'-dehydroxyphlorizin derivs. substituted on the B ring was prepd. and their effects on urinary glucose excretion were evaluated in rats. Introduction of only a small alkyl group at the 4'-position increased the activity, and 3-(benzo[b]furan-5-yl)-2',6'-dihydroxy-4'-methylpropiophenone 2'-O-β-D-glucopyranoside I (R = H) showed the most potent effect. To overcome hydrolysis by β-glucosidase in the digestive tract, the OH groups on the glucose moiety of I (R = H) were modified. Three prodrugs were more potent than the parent compd. by oral administration, and finally 3-(benzo[b]furan-5-yl)-2',6'-dihydroxy-4'-methylpropiophenone 2'-O-(6-O-methoxycarbonyl-β-D-glucopyranoside) I (R = CO2Me) was selected as a new promising candidate. This compd. was metabolized mainly by liver esterase to the active form, I (R = H) which was about 10 times more potent in inhibiting SGLT. In oral glucose tolerance test in db/db mice, I (R = CO2Me) dose-dependently suppressed the elevation of glucose levels. Single administration reduced hyperglycemia concurrently with increase of glucose excretion into urine in diabetic KK-Ay mice. Furthermore, I (R = CO2Me) suppressed the elevation of blood glucose levels but did not lower it below the normal level even in fasted conditions in KK-Ay mice. Addnl., long-term treatment dose-dependently reduced hyperglycemia and HbA1c in KK-Ay mice. These pharmacol. data strongly suggest that I (R = CO2Me) has a therapeutic potential in the treatment of NIDDM.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXnslSltbc%253D&md5=429449e4687602cac7866ef1bf279790

     
268. 268

     Ellsworth, B.; Washburn, W. N.; Sher, P. M.; Meng, W. C-Aryl Glucoside SGLT2 Inhibitors. International Patent WO2001027128, 2001.

     Google Scholar

     There is no corresponding record for this reference.

     
269. 269

     Nomura, S.; Sakamaki, S.; Hongu, M.; Kawanishi, E.; Koga, Y.; Sakamoto, T.; Yamamoto, Y.; Ueta, K.; Kimata, H.; Nakayama, K.; Tsuda-Tsukimoto, M. Discovery of Canagliflozin, a Novel C-Glucoside with Thiophene Ring, as Sodium-Dependent Glucose Cotransporter 2 Inhibitor for the Treatment of Type 2 Diabetes Mellitus. J. Med. Chem. 2010, 53, 6355– 6360,  DOI: 10.1021/jm100332n

     [ACS Full Text ], [CAS], Google Scholar

     269

     Discovery of Canagliflozin, a Novel C-Glucoside with Thiophene Ring, as Sodium-Dependent Glucose Co-transporter 2 Inhibitor for the Treatment of Type 2 Diabetes Mellitus

     Nomura, Sumihiro; Sakamaki, Shigeki; Hongu, Mitsuya; Kawanishi, Eiji; Koga, Yuichi; Sakamoto, Toshiaki; Yamamoto, Yasuo; Ueta, Kiichiro; Kimata, Hirotaka; Nakayama, Keiko; Tsuda-Tsukimoto, Minoru

     Journal of Medicinal Chemistry (2010), 53 (17), 6355-6360CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

     We discovered that aryl C-glucosides, e.g. I, bearing a heteroarom. ring formed metabolically more stable inhibitors for sodium-dependent glucose co-transporter 2 (SGLT2). Thiophene I (canagliflozin) was a highly potent and selective SGLT2 inhibitor and showed pronounced anti-hyperglycemic effects in high-fat diet fed KK (HF-KK) mice.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXpvVartbk%253D&md5=33c3a6bce5ae74799d051b6f8c06da7e

     
270. 270

     Akuta, N.; Kawamura, Y.; Watanabe, C.; Nishimura, A.; Okubo, M.; Mori, Y.; Fujiyama, S.; Sezaki, H.; Hosaka, T.; Kobayashi, M.; Kobayashi, M.; Saitoh, S.; Suzuki, F.; Suzuki, Y.; Arase, Y.; Ikeda, K.; Kumada, H. Impact of Sodium Glucose Cotransporter 2 Inhibitor on Histological Features and Glucose Metabolism of Non-Alcoholic Fatty Liver Disease Complicated by Diabetes Mellitus. Hepatol. Res. 2019, 49, 531– 539,  DOI: 10.1111/hepr.13304

     [Crossref], [PubMed], [CAS], Google Scholar

     270

     Impact of sodium glucose cotransporter 2 inhibitor on histological features and glucose metabolism of non-alcoholic fatty liver disease complicated by diabetes mellitus

     Akuta, Norio; Kawamura, Yusuke; Watanabe, Chizuru; Nishimura, Akihiro; Okubo, Minoru; Mori, Yasumichi; Fujiyama, Shunichiro; Sezaki, Hitomi; Hosaka, Tetsuya; Kobayashi, Masahiro; Kobayashi, Mariko; Saitoh, Satoshi; Suzuki, Fumitaka; Suzuki, Yoshiyuki; Arase, Yasuji; Ikeda, Kenji; Kumada, Hiromitsu

     Hepatology Research (2019), 49 (5), 531-539CODEN: HPRSFM; ISSN:1386-6346. (Wiley-Blackwell)

     Aim : The aim of this study was to investigate the therapeutic potential of sodium glucose cotransporter 2 inhibitor (SGLT2I) as an effective therapeutic option for non-alc. fatty liver disease (NAFLD). Methods : In this prospective study, nine patients with NAFLD complicated by type 2 diabetes mellitus (DM), were introduced to the regimen of canagliflozin 100 mg once daily for 24 wk and were evaluated by liver histol. at pretreatment and at 24 wk after the start of treatment. The primary outcome was histol. improvement, defined as a decrease in NAFLD activity score of one point or more without worsening in fibrosis stage. Glucose metab. was evaluated based on the meal tolerance test. The usefulness of extracellular and exosome microRNA-122 (miR-122) as early predictors of histol. improvement was investigated. Results : All of the nine patients achieved histol. improvement. Scores of steatosis, lobular inflammation, ballooning, and fibrosis stage decreased by 78%, 33%, 22%, and 33% at 24 wk compared to the pretreatment, resp. Six patients showed improvement in insulin resistance, and the other three patients showed partial improvement of insulin secretion function. Six patients, who showed a decrease in both extracellular and exosome miR-122 ratios (the ratio of miR-122 levels at 1 day after treatment to that at baseline), showed histol. improvement. Furthermore, one patient, who showed a decrease in exosome miR-122 ratios regardless of the increase in extracellular miR-122 ratios, also showed decreases in NAFLD activity score and fibrosis stage. Conclusion : A prospective study showed that SGLT2I for NAFLD complicated by DM improved histol. features in connection with glucose metab. This trial was registered as clin. trial UMIN000018166.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXpsVSns7Y%253D&md5=3f6a2efae3b02f98098cc17f94970f42

     
271. 271

     Itani, T.; Ishihara, T. Efficacy of Canagliflozin Against Nonalcoholic Fatty Liver Disease: A Prospective Cohort Study. Obes. Sci. Pract. 2018, 4, 477– 482,  DOI: 10.1002/osp4.294

     [Crossref], [PubMed], [CAS], Google Scholar

     271

     Efficacy of canagliflozin against nonalcoholic fatty liver disease: a prospective cohort study

     Itani Toshio; Ishihara Tomoaki

     Obesity science & practice (2018), 4 (5), 477-482 ISSN:.

     Background: Nonalcoholic fatty liver disease (NAFLD) is a common cause of chronic liver disease worldwide and is characterized by insulin resistance, hepatic steatosis and often prediabetes or diabetes. Canagliflozin, a selective sodium glucose cotransporter 2 inhibitor, is a new oral anti-diabetic drug that reduces hyperglycaemia by promoting urinary glucose excretion. Glycosuria produced by canagliflozin is associated with weight loss, mainly due to reduced fat volume and improve insulin resistance. Reduced body weight and improvement of insulin resistance by canagliflozin may be an effective treatment for NAFLD. Methods: Thirty-five patients with NAFLD (17 men and 18 women) were enrolled and administered canagliflozin (100 mg). Body weight and serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (γ-GTP), low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides (TG), blood sugar (BS), glycated haemoglobin (HbA1C), uric acid (UA) and ferritin, and fibrosis-4 (FIB-4) index values were measured at baseline and at 3-month and 6-month follow-up visits. Results: Body weight and serum levels of AST, ALT, γ-GTP, TG, UA, HbA1C, BS and ferritin decreased significantly after 3 and 6 months of canagliflozin treatment. Serum BS levels and FIB-4 index values decreased slightly following 3 months of treatment; these results reached significance after 6 months. Reduced serum ALT levels at 6 months were significantly correlated with baseline HbA1C and ferritin levels. Moreover, a significant correlation between reduced body weight and serum ALT levels was observed at 6 months. Decreased serum ALT levels were significantly correlated with decreased serum ferritin at 6 months. Conclusions: Canagliflozin significantly reduced the serum levels of BS, HbA1C, TG, UA and ferritin, as well as FIB-4 index values and body weight, with improved liver function. Sodium glucose cotransporter 2 inhibitors may be an important therapeutic modality for improving liver injury in NAFLD patients.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3cvhtVantQ%253D%253D&md5=eeeef35e61f6f8efa405fd9288c1bf49

     
272. 272

     Seko, Y.; Nishikawa, T.; Umemura, A.; Yamaguchi, K.; Moriguchi, M.; Yasui, K.; Kimura, M.; Iijima, H.; Hashimoto, T.; Sumida, Y.; Okanoue, T.; Itoh, Y. Efficacy and Safety of Canagliflozin in Type 2 Diabetes Mellitus Patients with Biopsy-Proven Nonalcoholic Steatohepatitis Classified as Stage 1–3 Fibrosis. Diabetes, Metab. Syndr. Obes.: Targets Ther. 2018, 11, 835– 843,  DOI: 10.2147/DMSO.S184767

     [Crossref], [PubMed], [CAS], Google Scholar

     272

     Efficacy and safety of canagliflozin in type 2 diabetes mellitus patients with biopsy-proven nonalcoholic steatohepatitis classified as stage 1-3 fibrosis

     Seko, Yuya; Nishikawa, Taichiro; Umemura, Atsushi; Yamaguchi, Kanji; Moriguchi, Michihisa; Yasui, Kohichiroh; Kimura, Mayumi; Iijima, Hiroaki; Hashimoto, Toshio; Sumida, Yoshio; Okanoue, Takeshi; Itoh, Yoshito

     Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy (2018), 11 (), 835-843CODEN: DMSOAD; ISSN:1178-7007. (Dove Medical Press Ltd.)

     Aim: Nonalcoholic fatty liver disease (NAFLD), including nonalcoholic steatohepatitis (NASH), is known to be assocd. with type 2 diabetes mellitus (T2DM) in high rate. The improvement in hepatic function due to sodium-glucose co-transporter 2 (SGLT2) inhibitors has been reported in T2DM patients with and without NAFLD. However, only a few studies have attempted to evaluate the role of SGLT2 inhibitors in T2DM patients with biopsy-proven NASH, and no detailed prospective studies including the individual hepatic fibrosis stage have been reported. Therefore, we investigated the effect of canagliflozin on hepatic function in T2DM patients with biopsy-confirmed NASH. Methods: T2DM patients with NASH (hepatic fibrosis stage 1-3 confirmed via liver biopsy, n=10) were enrolled and received canagliflozin (100 mg) once a day for 12 wk. The primary end point was change in serum alanine aminotransferase (ALT) levels from baseline to week 12. Secondary end points were liver function/fibrosis markers, metabolic parameters, and safety. Results: The change in ALT from baseline to week 12 was -23.9 U/L (95% CI -48.1 to 0.3, P=0.0526). Significant improvements in several hepatic function/fibrosis markers, such as aspartate aminotransferase, fibrosis-4 index, and FM-fibro index, and metabolic parameters including Hb A1c and body wt. were found. No serious or liver-related adverse events were reported. Regarding individual patients, different trends in ALT-lowering effects between stage 1 and stage 2/3 subjects were obsd.; the degree of ALT-lowering effect tended to be greater in the stage 1 group than in the stage 2/3 group. Conclusion: Our results suggest that canagliflozin is effective and well-tolerated in patients with T2DM and NASH. Canagliflozin may be useful for the treatment of T2DM patients with NASH, esp. those in early stages of NASH.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitFOhtb3M&md5=0cb9d1722e14037baf15a398a2c5e2eb

     
273. 273

     Meng, W.; Ellsworth, B. A.; Nirschl, A. A.; McCann, P. J.; Patel, M.; Girotra, R. N.; Wu, G.; Sher, P. M.; Morrison, E. P.; Biller, S. A.; Zahler, R.; Deshpande, P. P.; Pullockaran, A.; Hagan, D. L.; Morgan, N.; Taylor, J. R.; Obermeier, M. T.; Humphreys, W. G.; Khanna, A.; Discenza, L.; Robertson, J. G.; Wang, A.; Han, S.; Wetterau, J. R.; Janovitz, E. B.; Flint, O. P.; Whaley, J. M.; Washburn, W. N. Discovery of Dapagliflozin: A Potent, Selective Renal Sodium-Dependent Glucose Cotransporter 2 (SGLT2) Inhibitor for the Treatment of Type 2 Diabetes. J. Med. Chem. 2008, 51, 1145– 1149,  DOI: 10.1021/jm701272q

     [ACS Full Text ], [CAS], Google Scholar

     273

     Discovery of Dapagliflozin: A Potent, Selective Renal Sodium-Dependent Glucose Cotransporter 2 (SGLT2) Inhibitor for the Treatment of Type 2 Diabetes

     Meng, Wei; Ellsworth, Bruce A.; Nirschl, Alexandra A.; McCann, Peggy J.; Patel, Manorama; Girotra, Ravindar N.; Wu, Gang; Sher, Philip M.; Morrison, Eamonn P.; Biller, Scott A.; Zahler, Robert; Deshpande, Prashant P.; Pullockaran, Annie; Hagan, Deborah L.; Morgan, Nathan; Taylor, Joseph R.; Obermeier, Mary T.; Humphreys, William G.; Khanna, Ashish; Discenza, Lorell; Robertson, James G.; Wang, Aiying; Han, Songping; Wetterau, John R.; Janovitz, Evan B.; Flint, Oliver P.; Whaley, Jean M.; Washburn, William N.

     Journal of Medicinal Chemistry (2008), 51 (5), 1145-1149CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

     The C-aryl glucoside 6 (dapagliflozin) was identified as a potent and selective hSGLT2 inhibitor which reduced blood glucose levels in a dose-dependent manner by as much as 55% in hyperglycemic streptozotocin (STZ) rats. These findings, combined with a favorable ADME profile, have prompted clin. evaluation of dapagliflozin for the treatment of type 2 diabetes.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhvFWgtrY%253D&md5=8b31ec17acef23a7507ce6a7d9184eb9

     
274. 274

     Jikura, H.; Fushimi, N.; Nishimura, T.; Tatani, K.; Katsuno, K. Glucopyranosyloxy Benzylbenzene Derivatives, Medicinal Compositions Containing the Same and Intermediates for the Preparation of the Derivatives. International Patent WO2001068660, 2001.

     Google Scholar

     There is no corresponding record for this reference.

     
275. 275

     Choi, D. H.; Jung, C. H.; Mok, J. O.; Kim, C. H.; Kang, S. K.; Kim, B. Y. Effect of Dapagliflozin on Alanine Aminotransferase Improvement in Type 2 Diabetes Mellitus with Non-alcoholic Fatty Liver Disease. Endocrinol. Metab. (Seoul) 2018, 33, 387– 394,  DOI: 10.3803/EnM.2018.33.3.387

     [Crossref], [PubMed], [CAS], Google Scholar

     275

     Effect of dapagliflozin on alanine aminotransferase improvement in type 2 diabetes mellitus with nonalcoholic fatty liver disease

     Choi, Dug-Hyun; Jung, Chan-Hee; Mok, Ji-Oh; Kim, Chul-Hee; Kang, Sung-Koo; Kim, Bo-Yeon

     Endocrinology and Metabolism (Seoul, Republic of Korea) (2018), 33 (3), 387-394CODEN: EMSRCZ; ISSN:2093-5978. (Korean Endocrine Society)

     Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are expected to improve the liver function of patients with non-alc. fatty liver disease (NAFLD) combined type 2 diabetes mellitus (T2DM) by its characteristic mechanism. This study was designed to investigate the effect of dapagliflozin, one of the SGLT2i, on the liver function of T2DM with NAFLD when combined with metformin. Among patients who received dual oral hypoglycemic agents within the 3 mo of diagnosing NAFLD, patients who had abnormal alanine aminotransferase (ALT) level (> 40 IU/L) were included. Patients were divided into two groups: metformin + dapagliflozin group and metformin + dipeptidyl peptidase-4 inhibitors (DPP4i) group. Demog. data, biochem. data and the clin. and treatment histories of all patients were reviewed. A total of 102 patients were included (dapagliflozin group, n = 50; DPP4i group, n = 52). Dapagliflozin group showed more wt. loss and more ALT decline than DPP4i group (-2.9 kg vs. -0.4 kg, P = 0.005; -21.1 U/L vs. -9.5 U/L, P = 0.008, resp.) and the proportion of patients with ALT normalization after treatment was also significantly higher in the dapagliflozin group (80.0% vs. 61.5%, P = 0.041). The effect of dapagliflozin with metformin on ALT normalization remained significant after adjustment for confounding variables including body wt. loss (odds ratio, 3.489; P = 0.046). ALT improvement was statistically significant in the dapagliflozin than the DPP4i when combined with metformin and the result was consistent after adjustment for confounding variables including body wt. loss.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhs1ejsrrL&md5=b44a2d22ccd3be7fd322073b998b6641

     
276. 276

     Tobita, H.; Sato, S.; Miyake, T.; Ishihara, S.; Kinoshita, Y. Effects of Dapagliflozin on Body Composition and Liver Tests in Patients with Nonalcoholic Steatohepatitis Associated with Type 2 Diabetes Mellitus: A Prospective, Open-label, Uncontrolled Study. Curr. Ther. Res. 2017, 87, 13– 19,  DOI: 10.1016/j.curtheres.2017.07.002

     [Crossref], [PubMed], [CAS], Google Scholar

     276

     Effects of Dapagliflozin on Body Composition and Liver Tests in Patients with Nonalcoholic Steatohepatitis Associated with Type 2 Diabetes Mellitus: A Prospective, Open-label, Uncontrolled Study

     Tobita, Hiroshi; Sato, Shuichi; Miyake, Tatsuya; Ishihara, Shunji; Kinoshita, Yoshikazu

     Current Therapeutic Research (2017), 87 (), 13-19CODEN: CTCEA9; ISSN:0011-393X. (Elsevier B.V.)

     Nonalcoholic steatohepatitis (NASH) is an active form of nonalcoholic fatty liver disease. Risk factors for NASH include type 2 diabetes mellitus (T2DM) and obesity. Sodium-glucose cotransporter 2 (SGLT2) inhibitors used to treat T2DM prevent glucose reabsorption in the kidney and increase glucose urinary excretion. Dapagliflozin is a potent, selective SGLT2 inhibitor that reduces hyperglycemia in patients with T2DM and has been demonstrated to reduce some complications assocd. with NASH in rodent models. To assess the efficacy and safety profile of dapagliflozin for the treatment of NASH-assocd. with T2DM. In this single-arm, nonrandomized, open-label study, 16 patients with percutaneous liver biopsy-confirmed NASH and T2DM were enrolled to be prescribed dapagliflozin 5 mg/d for 24 wk. Of these, 11 patients were evaluable. Patients with chronic liver disease other than NASH were excluded. Body compn., lab. variables related to liver tests and metab., and glucose homeostasis were assessed at baseline and periodically during the study. Changes from baseline were evaluated with the Wilcoxon signed-rank test. Administration of dapagliflozin for 24 wk was assocd. with significant decreases in body mass index (P < 0.01), waist circumference (P < 0.01), and waist-to-hip ratio (P < 0.01). Changes in body compn. were driven by redns. in body fat mass (P< 0.01) and percent body fat (P < 0.01), without changes in lean mass or total body water. Liver tests (ie, serum concns. of aspartate aminotransferase, alanine aminotransferase, ferritin, and type IV collagen 7S) also significantly improved during the study. Insulin concns. decreased (P < 0.01 by Week 24) in combination with significant redns. in fasting plasma glucose (P < 0.01) and glycated Hb (P < 0.01) levels and increases in adiponectin (P < 0.01) levels from Week 4 onward. Dapagliflozin was assocd. with improvements in body compn., most likely a redn. in visceral fat, which occurred together with improvements in liver tests and metabolic variables in patients with NASH-assocd. with T2DM.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtlGrs7rM&md5=7b2d323d7a6f06f114008761132f1c0f

     
277. 277

     Shimizu, M.; Suzuki, K.; Kato, K.; Jojima, T.; Iijima, T.; Murohisa, T.; Iijima, M.; Takekawa, H.; Usui, I.; Hiraishi, H.; Aso, Y. Evaluation of the Effects of Dapagliflozin, a Sodium-Glucose Co-Transporter-2 Inhibitor, on Hepatic Steatosis and Fibrosis Using Transient Elastography in Patients with Type 2 Diabetes and Non-Alcoholic Fatty Liver Disease. Diabetes, Obes. Metab. 2019, 21, 285– 292,  DOI: 10.1111/dom.13520

     [Crossref], [PubMed], [CAS], Google Scholar

     277

     Evaluation of the effects of dapagliflozin, a sodium-glucose co-transporter-2 inhibitor, on hepatic steatosis and fibrosis using transient elastography in patients with type 2 diabetes and non-alcoholic fatty liver disease

     Shimizu, Masanori; Suzuki, Kunihiro; Kato, Kanako; Jojima, Teruo; Iijima, Toshie; Murohisa, Toshimitsu; Iijima, Makoto; Takekawa, Hidehiro; Usui, Isao; Hiraishi, Hideyuki; Aso, Yoshimasa

     Diabetes, Obesity and Metabolism (2019), 21 (2), 285-292CODEN: DOMEF6; ISSN:1462-8902. (Wiley-Blackwell)

     Aims : To investigate the effects of dapagliflozin on liver steatosis and fibrosis evaluated in patients with type 2 diabetes and non-alc. fatty liver disease (NAFLD). Materials and methods : In a randomized, active-controlled, open-label trial, 57 patients with type 2 diabetes and NAFLD were randomized to a dapagliflozin group (5 mg/d; n = 33) or a control group (n = 24) and were treated for 24 wk. Hepatic steatosis and fibrosis were assessed using transient elastog. to measure controlled attenuation parameter (CAP) and liver stiffness, resp. Results : Baseline liver stiffness measurement (LSM) was pos. correlated with several markers and scoring systems for liver fibrosis. In week 24, there was a significant decrease in CAP from 314 ± 61 to 290 ± 73 dB/m (P = 0.0424) in the dapagliflozin group, while there was no significant change in the control group. In addn., LSM tended to decrease from 9.49 ± 6.05 to 8.01 ± 5.78 kPa in the dapagliflozin group. In 14 patients from this group with LSM values ≥8.0 kPa, indicating significant liver fibrosis, LSM decreased significantly from 14.7 ± 5.7 to 11.0 ± 7.3 kPa (P = 0.0158). Furthermore, serum alanine aminotransferase and γ-glutamyltranspeptidase levels decreased in the dapagliflozin group, but not in the control group, and visceral fat mass was significantly reduced in the dapagliflozin group. Conclusions : Based on these findings, the sodium-glucose co-transporter-2 inhibitor dapagliflozin improves liver steatosis in patients with type 2 diabetes and NAFLD, and attenuates liver fibrosis only in patients with significant liver fibrosis, although the possibility cannot be excluded that a redn. in body wt. or visceral adipose tissue by dapagliflozin may be assocd. with a decrease of liver steatosis or fibrosis.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXnt1WgtQ%253D%253D&md5=229afd2eb9199d367b20b6459cf19f92

     
278. 278

     Grempler, R.; Thomas, L.; Eckhardt, M.; Himmelsbach, F.; Sauer, A.; Sharp, D. E.; Bakker, R. A.; Mark, M.; Klein, T.; Eickelmann, P. Empagliflozin, a Novel Selective Sodium Glucose Cotransporter-2 (SGLT-2) Inhibitor: Characterisation and Comparison with Other SGLT-2 Inhibitors. Diabetes, Obes. Metab. 2012, 14, 83– 90,  DOI: 10.1111/j.1463-1326.2011.01517.x

     [Crossref], [PubMed], [CAS], Google Scholar

     278

     Empagliflozin, a novel selective sodium glucose cotransporter-2 (SGLT-2) inhibitor: characterisation and comparison with other SGLT-2 inhibitors

     Grempler, R.; Thomas, L.; Eckhardt, M.; Himmelsbach, F.; Sauer, A.; Sharp, D. E.; Bakker, R. A.; Mark, M.; Klein, T.; Eickelmann, P.

     Diabetes, Obesity and Metabolism (2012), 14 (1), 83-90CODEN: DOMEF6; ISSN:1462-8902. (Wiley-Blackwell)

     Aims: Empagliflozin is a selective sodium glucose cotransporter-2 (SGLT-2) inhibitor in clin. development for the treatment of type 2 diabetes mellitus. This study assessed pharmacol. properties of empagliflozin in vitro and pharmacokinetic properties in vivo and compared its potency and selectivity with other SGLT-2 inhibitors. Methods: [14C]-alpha-Me glucopyranoside (AMG) uptake expts. were performed with stable cell lines over-expressing human (h) SGLT-1, 2 and 4. Two new cell lines over-expressing hSGLT-5 and hSGLT-6 were established and [14C]-mannose and [14C]-myo-inositol uptake assays developed. Binding kinetics were analyzed using a radioligand binding assay with [3H]-labeled empagliflozin and HEK293-hSGLT-2 cell membranes. Acute in vivo assessment of pharmacokinetics was performed with normoglycemic beagle dogs and Zucker diabetic fatty (ZDF) rats. Results: Empagliflozin has an IC50 of 3.1 nM for hSGLT-2. Its binding to SGLT-2 is competitive with glucose (half-life approx. 1 h). Compared with other SGLT-2 inhibitors, empagliflozin has a high degree of selectivity over SGLT-1, 4, 5 and 6. Species differences in SGLT-1 selectivity were identified. Empagliflozin pharmacokinetics in ZDF rats were characterised by moderate total plasma clearance (CL) and bioavailability (BA), while in beagle dogs CL was low and BA was high. Conclusions: Empagliflozin is a potent and competitive SGLT-2 inhibitor with an excellent selectivity profile and the highest selectivity window of the tested SGLT-2 inhibitors over hSGLT-1. Empagliflozin represents an innovative therapeutic approach to treat diabetes.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhvFOmsb8%253D&md5=c892658855962a196ef5b5e1e6194ff0

     
279. 279

     Lai, L. L.; Vethakkan, S. R.; Nik Mustapha, N. R.; Mahadeva, S.; Chan, W. K. Empagliflozin for the Treatment of Nonalcoholic Steatohepatitis in Patients with Type 2 Diabetes Mellitus. Dig. Dis. Sci. 2019, 1– 9,  DOI: 10.1007/s10620-019-5477-1

     [Crossref], [PubMed], Google Scholar

     There is no corresponding record for this reference.

     
280. 280

     Kuchay, M. S.; Krishan, S.; Mishra, S. K.; Farooqui, K. J.; Singh, M. K.; Wasir, J. S.; Bansal, B.; Kaur, P.; Jevalikar, G.; Gill, H. K.; Choudhary, N. S.; Mithal, A. Effect of Empagliflozin on Liver Fat in Patients with Type 2 Diabetes and Nonalcoholic Fatty Liver Disease: A Randomized Controlled Trial (E-LIFT Trial). Diabetes Care 2018, 41, 1801– 1808,  DOI: 10.2337/dc18-0165

     [Crossref], [PubMed], [CAS], Google Scholar

     280

     Effect of empagliflozin on liver fat in patients with type 2 diabetes and nonalcoholic fatty liver disease: a randomized controlled trial (E-LIFT Trial)

     Kuchay, Mohammad Shafi; Krishan, Sonal; Mishra, Sunil Kumar; Farooqui, Khalid Jamal; Singh, Manish Kumar; Wasir, Jasjeet Singh; Bansal, Beena; Kaur, Parjeet; Jevalikar, Ganesh; Gill, Harmendeep Kaur; Choudhary, Narendra Singh; Mithal, Ambrish

     Diabetes Care (2018), 41 (8), 1801-1808CODEN: DICAD2; ISSN:0149-5992. (American Diabetes Association, Inc.)

     OBJECTIVE Sodium-glucose cotransporter 2 (SGLT-2) inhibitors have been shown to reduce liver fat in rodentmodels. Data regarding the effect of SGLT-2 inhibitors on human liver fat are scarce. This study examd. the effect of empagliflozin (an SGLT-2 inhibitor) on liver fat in patients with type 2 diabetes and nonalcoholic fatty liver disease (NAFLD) by using MRI-derived proton d. fat fraction (MRI-PDFF). RESEARCH DESIGN AND METHODS Fifty patients with type 2 diabetes and NAFLD were randomly assigned to either the empagliflozin group (std. treatment for type 2 diabetes plus empagliflozin 10 mg daily) or the control group (std. treatment without empagliflozin) for 20 wk. Change in liver fat was measured by MRI-PDFF. Secondary outcome measures were change in alanine transaminase (ALT), aspartate transaminase (AST), and g-glutamyl transferase (GGT) levels. RESULTS When included in the std. treatment for type 2 diabetes, empagliflozin was significantly better at reducing liver fat (mean MRI-PDFF difference between the empagliflozin and control groups 24.0%; P < 0.0001). Compared with baseline, significant redn. was found in the end-of-treatment MRI-PDFF for the empagliflozin group (16.2% to 11.3%; P < 0.0001) and a nonsignificant change was found in the control group (16.4% to 15.5%; P = 0.057). The two groups showed a significant difference for change in serum ALT level (P = 0.005) and nonsignificant differences for AST (P = 0.212) and GGT (P = 0.057) levels. CONCLUSIONS When included in the std. treatment for type 2 diabetes, empagliflozin reduces liver fat and improves ALT levels in patients with type 2 diabetes and NAFLD.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitlWhsbo%253D&md5=241ca4a30401eb548178eb1124b81c45

     
281. 281

     Imamura, M.; Nakanishi, K.; Suzuki, T.; Ikegai, K.; Shiraki, R.; Ogiyama, T.; Murakami, T.; Kurosaki, E.; Noda, A.; Kobayashi, Y.; Yokota, M.; Koide, T.; Kosakai, K.; Ohkura, Y.; Takeuchi, M.; Tomiyama, H.; Ohta, M. Discovery of Ipragliflozin (ASP1941): A Novel C-Glucoside with Benzothiophene Structure as a Potent and Selective Sodium Glucose Co-Transporter 2 (SGLT2) Inhibitor for the Treatment of Type 2 Diabetes Mellitus. Bioorg. Med. Chem. 2012, 20, 3263– 3279,  DOI: 10.1016/j.bmc.2012.03.051

     [Crossref], [PubMed], [CAS], Google Scholar

     281

     Discovery of Ipragliflozin (ASP1941): A novel C-glucoside with benzothiophene structure as a potent and selective sodium glucose co-transporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes mellitus

     Imamura, Masakazu; Nakanishi, Keita; Suzuki, Takayuki; Ikegai, Kazuhiro; Shiraki, Ryota; Ogiyama, Takashi; Murakami, Takeshi; Kurosaki, Eiji; Noda, Atsushi; Kobayashi, Yoshinori; Yokota, Masayuki; Koide, Tomokazu; Kosakai, Kazuhiro; Ohkura, Yasufumi; Takeuchi, Makoto; Tomiyama, Hiroshi; Ohta, Mitsuaki

     Bioorganic & Medicinal Chemistry (2012), 20 (10), 3263-3279CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)

     A series of C-glucosides with various heteroaroms. has been synthesized and its inhibitory activity toward SGLTs was evaluated. Upon screening several compds., the benzothiophene deriv. I (R =H) was found to have potent inhibitory activity against SGLT2 and good selectivity vs. SGLT1. Through further optimization of 14a, a novel benzothiophene deriv. I (R = F) (ipragliflozin, ASP1941) was discovered as a highly potent and selective SGLT2 inhibitor that reduced blood glucose levels in a dose-dependent manner in diabetic models KK-Ay mice and STZ rats.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XlsFCqtLs%253D&md5=3552a64a85d0f769a10e1ad8e1dd8736

     
282. 282

     Kakinuma, H.; Oi, T.; Hashimoto-Tsuchiya, Y.; Arai, M.; Kawakita, Y.; Fukasawa, Y.; Iida, I.; Hagima, N.; Takeuchi, H.; Chino, Y.; Asami, J.; Okumura-Kitajima, L.; Io, F.; Yamamoto, D.; Miyata, N.; Takahashi, T.; Uchida, S.; Yamamoto, K. (1S)-1,5-Anhydro-1-[5-(4-ethoxybenzyl)-2-methoxy-4-methylphenyl]-1-thio-D-glucito l (TS-071) is a Potent, Selective Sodium-Dependent Glucose Cotransporter 2 (SGLT2) Inhibitor for Type 2 Diabetes Treatment. J. Med. Chem. 2010, 53, 3247– 3261,  DOI: 10.1021/jm901893x

     [ACS Full Text ], [CAS], Google Scholar

     282

     (1S)-1,5-Anhydro-1-[5-(4-ethoxybenzyl)-2-methoxy-4-methylphenyl]-1-thio-D-glucitol (TS-071) is a Potent, Selective Sodium-Dependent Glucose Cotransporter 2 (SGLT2) Inhibitor for Type 2 Diabetes Treatment

     Kakinuma, Hiroyuki; Oi, Takahiro; Hashimoto-Tsuchiya, Yuko; Arai, Masayuki; Kawakita, Yasunori; Fukasawa, Yoshiki; Iida, Izumi; Hagima, Naoko; Takeuchi, Hiroyuki; Chino, Yukihiro; Asami, Jun; Okumura-Kitajima, Lisa; Io, Fusayo; Yamamoto, Daisuke; Miyata, Noriyuki; Takahashi, Teisuke; Uchida, Saeko; Yamamoto, Koji

     Journal of Medicinal Chemistry (2010), 53 (8), 3247-3261CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

     Derivs. of a novel scaffold, C-Ph 1-thio-D-glucitol, were prepd. and evaluated for sodium-dependent glucose cotransporter (SGLT) 2 and SGLT1 inhibition activities. Optimization of substituents on the arom. rings afforded five compds. with potent and selective SGLT2 inhibition activities. The compds. were evaluated for in vitro human metabolic stability, human serum protein binding (SPB), and Caco-2 permeability. Of them, (1S)-1,5-anhydro-1-[5-(4-ethoxybenzyl)-2-methoxy-4-methylphenyl]-1-thio-D-glucitol (3p) (I) exhibited potent SGLT2 inhibition activity (IC50 = 2.26 nM), with 1650-fold selectivity over SGLT1. Compd. 3p showed good metabolic stability toward cryo-preserved human hepatic clearance, lower SPB, and moderate Caco-2 permeability. Since 3p should have acceptable human pharmacokinetics (PK) properties, it could be a clin. candidate for treating type 2 diabetes. We obsd. that compd. 3p exhibits a blood glucose lowering effect, excellent urinary glucose excretion properties, and promising PK profiles in animals. Phase II clin. trials of 3p (TS-071) are currently ongoing.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXjs1Wrsrs%253D&md5=7b9954e5635d73c5edacb119b324a9b0

     
283. 283

     Shibuya, T.; Fushimi, N.; Kawai, M.; Yoshida, Y.; Hachiya, H.; Ito, S.; Kawai, H.; Ohashi, N.; Mori, A. Luseogliflozin Improves Liver Fat Deposition Compared to Metformin in Type 2 Diabetes Patients with Non-Alcoholic Fatty Liver Disease: A Prospective Randomized Controlled Pilot Study. Diabetes, Obes. Metab. 2018, 20, 438– 442,  DOI: 10.1111/dom.13061

     [Crossref], [PubMed], [CAS], Google Scholar

     283

     Luseogliflozin improves liver fat deposition compared to metformin in type 2 diabetes patients with non-alcoholic fatty liver disease: A prospective randomized controlled pilot study

     Shibuya, Takashi; Fushimi, Nobutoshi; Kawai, Miyuka; Yoshida, Yohei; Hachiya, Hiroki; Ito, Shun; Kawai, Hiromi; Ohashi, Noritsugu; Mori, Akihiro

     Diabetes, Obesity and Metabolism (2018), 20 (2), 438-442CODEN: DOMEF6; ISSN:1462-8902. (Wiley-Blackwell)

     This study aimed to assess the effect of luseogliflozin on liver fat deposition and compare luseogliflozin to metformin in type 2 diabetes (T2D) patients with non-alc. fatty liver disease (NAFLD). Thirty-two T2D patients with NAFLD diagnosed by computed tomog. or abdominal sonog. were recruited. Participants were randomly assigned to receive either luseogliflozin (2.5 mg, newly administered) or metformin (1500 mg, newly or addnl. administrated). Data on the liver-to-spleen attenuation ratio (L/S), visceral fat area, body mass index, glycated Hb (HbA1c), alanine aminotransferase (ALT), fasting plasma glucose, C-peptide immunoreactivity (CPR), and CPR index were collected at baseline and after 6 mo. The change in L/S was significantly greater in the luseogliflozin group than in the metformin group. Similarly, the changes in the visceral fat area, HbA1c, and body mass index were significantly greater in the luseogliflozin group than in the metformin group. The changes in ALT, fasting glucose, CPR, and CPR index were not significant in both groups. In conclusion, luseogliflozin significantly reduced liver fat deposition as compared to metformin, which may indicate clin. relevant benefits for NAFLD.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhsVaktLc%253D&md5=202d5b117bb41115199d107f9b56667c

     
284. 284

     Sumida, Y.; Murotani, K.; Saito, M.; Tamasawa, A.; Osonoi, Y.; Yoneda, M.; Osonoi, T. Effect of Luseogliflozin on Hepatic Fat Content in Type 2 Diabetes Patients with Non-Alcoholic Fatty Liver Disease: A Prospective, Single-Arm Trial (LEAD trial). Hepatol. Res. 2019, 49, 64– 71,  DOI: 10.1111/hepr.13236

     [Crossref], [PubMed], [CAS], Google Scholar

     284

     Effect of luseogliflozin on hepatic fat content in type 2 diabetes patients with non-alcoholic fatty liver disease: A prospective, single-arm trial (LEAD trial)

     Sumida, Yoshio; Murotani, Kenta; Saito, Miyoko; Tamasawa, Atsuko; Osonoi, Yusuke; Yoneda, Masashi; Osonoi, Takeshi

     Hepatology Research (2019), 49 (1), 64-71CODEN: HPRSFM; ISSN:1386-6346. (Wiley-Blackwell)

     Aims : No pharmacol. therapies are approved for non-alc. fatty liver disease (NAFLD). Luseogliflozin, a sodium glucose cotransporter 2 inhibitor, has been developed for the treatment of adults with type 2 diabetes (T2DM). The aim of this prospective, single-arm study is to evaluate the efficacy of luseogliflozin on hepatic fat content and glycated Hb (HbA1c) in T2DM patients with NAFLD. Methods : Forty T2DM patients with NAFLD were treated with luseogliflozin 2.5 mg/day for 24 wk. Primary end-points were changes in HbA1c and hepatic steatosis evaluated by magnetic resonance imaging-hepatic fat fraction from baseline. Secondary end-points were changes in metabolic and hepatic function-related parameters, including hepatic fibrosis markers (Fibrosis-4 index, NAFLD fibrosis score, type IV collagen 7S. and Wisteria floribunda agglutinin-pos. Mac-2 binding protein). Results : Not only HbA1c and transaminase activities but also hepatic fat content were significantly decreased after 24 wk of therapy with luseogliflozin. The redn. of hepatic fat content was significantly correlated with the redn. of alanine aminotransferase. Although hepatic fibrosis markers were unchanged, serum ferritin levels reduced and serum albumin significantly increased after the treatment. Conclusion : Luseogliflozin can be a novel promising agent for the treatment of T2DM patients with NAFLD. Prospective randomized controlled trials are warranted to confirm this impact of luseogliflozin onT2DM with NAFLD.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtVags74%253D&md5=6ab44b55989c8e7aa09805fd3ae954ff

     
285. 285

     Iruarrizaga-Lejarreta, M.; Varela-Rey, M.; Fernandez-Ramos, D.; Martinez-Arranz, I.; Delgado, T. C.; Simon, J.; Juan, V. G.; delaCruz-Villar, L.; Azkargorta, M.; Lavin, J. L.; Mayo, R.; Van Liempd, S. M.; Aurrekoetxea, I.; Buque, X.; Cave, D. D.; Pena, A.; Rodriguez-Cuesta, J.; Aransay, A. M.; Elortza, F.; Falcon-Perez, J. M.; Aspichueta, P.; Hayardeny, L.; Noureddin, M.; Sanyal, A. J.; Alonso, C.; Anguita, J.; Martinez-Chantar, M. L.; Lu, S. C.; Mato, J. M. Role of Aramchol in Steatohepatitis and Fibrosis in Mice. Hepatol. Commun. 2017, 1, 911– 927,  DOI: 10.1002/hep4.1107

     [Crossref], [PubMed], [CAS], Google Scholar

     285

     Role of aramchol in steatohepatitis and fibrosis in mice

     Iruarrizaga-Lejarreta, Marta; Varela-Rey, Marta; Fernandez-Ramos, David; Martinez-Arranz, Ibon; Delgado, Teresa C.; Simon, Jorge; Gutierrez-de Juan, Virginia; dela Cruz-Villar, Laura; Azkargorta, Mikel; Lavin, Jose L.; Mayo, Rebeca; Van Liempd, Sebastiaan M.; Aurrekoetxea, Igor; Buque, Xabier; Delle Cave, Donatella; Pena, Arantza; Rodriguez-Cuesta, Juan; Aransay, Ana M.; Elortza, Felix; Falcon-Perez, Juan M.; Aspichueta, Patricia; Hayardeny, Liat; Noureddin, Mazen; Sanyal, Arun J.; Alonso, Cristina; Anguita, Juan; Martinez-Chantar, Maria Luz; Lu, Shelly C.; Mato, Jose M.

     Hepatology Communications (2017), 1 (9), 911-927CODEN: HCEOAJ; ISSN:2471-254X. (John Wiley & Sons, Inc.)

     Nonalcoholic steatohepatitis (NASH) is the advanced form of nonalcoholic fatty liver disease (NAFLD) that sets the stage for further liver damage. The mechanism for the progression of NASH involves multiple parallel hits, including oxidative stress, mitochondrial dysfunction, inflammation, and others. Manipulation of any of these pathways may be an approach to prevent NASH development and progression. Arachidyl-amido cholanoic acid (Aramchol) is presently in a phase IIb NASH study. The aim of the present study was to investigate Aramchol's mechanism of action and its effect on fibrosis using the methionine- and choline-deficient (MCD) diet model of NASH. We collected liver and serum from mice fed an MCD diet contg. 0.1% methionine (0.1MCD) for 4 wk; these mice developed steatohepatitis and fibrosis. We also collected liver and serum from mice receiving a control diet, and metabolomes and proteomes were detd. for both groups. The 0.1MCD-fed mice were given Aramchol (5 mg/kg/day for the last 2 wk), and liver samples were analyzed histol. Aramchol administration reduced features of steatohepatitis and fibrosis in 0.1MCD-fed mice. Aramchol down-regulated stearoyl-coenyzme A desaturase 1, a key enzyme involved in triglyceride biosynthesis and the loss of which enhances fatty acid β-oxidn. Aramchol increased the flux through the transsulfuration pathway, leading to a rise in glutathione (GSH) and the GSH/oxidized GSH ratio, the main cellular antioxidant that maintains intracellular redox status. Comparison of the serum metabolomic pattern between 0.1MCD-fed mice and patients with NAFLD showed a substantial overlap. Conclusion: Aramchol treatment improved steatohepatitis and fibrosis by 1) decreasing stearoyl-coenyzme A desaturase 1 and 2) increasing the flux through the transsulfuration pathway maintaining cellular redox homeostasis. We also demonstrated that the 0.1MCD model resembles the metabolic phenotype obsd. in about 50% of patients with NAFLD, which supports the potential use of Aramchol in NASH treatment. (Hepatol. Communications 2017;1:911-927).

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXjs1Kiu7s%253D&md5=1794a3c4459be88ae901d4143d899661

     
286. 286

     Safadi, R.; Konikoff, F. M.; Mahamid, M.; Zelber-Sagi, S.; Halpern, M.; Gilat, T.; Oren, R.; FLORA Group The Fatty Acid-Bile Acid Conjugate Aramchol Reduces Liver Fat Content in Patients with Nonalcoholic Fatty Liver Disease. Clin. Gastroenterol. Hepatol. 2014, 12, 2085– 2091,  DOI: 10.1016/j.cgh.2014.04.038

     [Crossref], [PubMed], [CAS], Google Scholar

     286

     The Fatty Acid-Bile Acid Conjugate Aramchol Reduces Liver Fat Content in Patients With Nonalcoholic Fatty Liver Disease

     Safadi, Rifaat; Konikoff, Fred M.; Mahamid, Mahmud; Zelber-Sagi, Shira; Halpern, Maya; Gilat, Tuvia; Oren, Ran

     Clinical Gastroenterology and Hepatology (2014), 12 (12), 2085-2091.e1CODEN: CGHLAW; ISSN:1542-3565. (Elsevier)

     We investigated the effects of the fatty acid-bile acid conjugate 3β-arachidyl-amido, 7α-12α-dihydroxy, 5β-cholan-24-oic acid (Aramchol; Trima Israel Pharmaceutical Products Ltd, Maabarot, Israel) in a phase 2 trial of patients with nonalcoholic fatty liver disease (NAFLD).We performed a randomized, double-blind, placebo-controlled trial of 60 patients with biopsy-confirmed NAFLD (6 with nonalcoholic steatohepatitis) at 10 centers in Israel. Patients were given Aramchol (100 or 300 mg) or placebo once daily for 3 mo (n = 20/group). The main end point was the difference between groups in the change in liver fat content according to magnetic resonance spectroscopy. The secondary end points focused on the differences between groups in alterations of liver enzyme levels, levels of adiponectin, homeostasis model assessment scores, and endothelial function.No serious or drug-related adverse events were obsd. in the 58 patients who completed the study. Over 3 mo, liver fat content decreased by 12.57% ± 22.14% in patients given 300 mg/day Aramchol, but increased by 6.39% ± 36.27% in the placebo group (P = .02 for the difference between groups, adjusted for age, sex, and body mass index). Liver fat content decreased in the 100-mg Aramchol group, by 2.89% ± 28.22%, but this change was nonsignificant (P = .35), indicating a dose-response relationship (P for trend = .01). Groups given Aramchol had nonsignificant improvements over time in endothelial function and levels of alanine aminotransferase and adiponectin, but homeostasis model assessment scores did not change. The appropriateness of a single daily dose was confirmed by pharmacokinetic anal.Three months' administration of the fatty acid-bile acid conjugate Aramchol is safe, tolerable, and significantly reduces liver fat content in patients with NAFLD. The redn. in liver fat content occurred in a dose-dependent manner and was assocd. with a trend of metabolic improvements, indicating that Aramchol might be used for the treatment of fatty liver disease. ClinicalTrials.gov no.: NCT01094158.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtFWisL7F&md5=328ff3f28a5d39e4213dd994d22962bb

     
287. 287

     Dobrzyn, P.; Dobrzyn, A.; Miyazaki, M.; Cohen, P.; Asilmaz, E.; Hardie, D. G.; Friedman, J. M.; Ntambi, J. M. Stearoyl-CoA Desaturase 1 Deficiency Increases Fatty Acid Oxidation By Activating AMP-Activated Protein Kinase in Liver. Proc. Natl. Acad. Sci. U. S. A. 2004, 101, 6409– 6414,  DOI: 10.1073/pnas.0401627101

     [Crossref], [PubMed], [CAS], Google Scholar

     287

     Stearoyl-CoA desaturase 1 deficiency increases fatty acid oxidation by activating AMP-activated protein kinase in liver

     Dobrzyn, Pawel; Dobrzyn, Agnieszka; Miyazaki, Makoto; Cohen, Paul; Asilmaz, Esra; Hardie, D. Grahame; Friedman, Jeffrey M.; Ntambi, James M.

     Proceedings of the National Academy of Sciences of the United States of America (2004), 101 (17), 6409-6414CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)

     Stearoyl-CoA desaturase (SCD) catalyzes the rate-limiting step in the biosynthesis of monounsatd. fatty acids. Mice with a targeted disruption of the SCD1 isoform have reduced body adiposity, increased energy expenditure, and up-regulated expression of several genes encoding enzymes of fatty acid β-oxidn. in liver. The mechanisms by which SCD deficiency leads to these metabolic changes are presently unknown. Here we show that the phosphorylation and activity of AMP-activated protein kinase (AMPK), a metabolic sensor that regulates lipid metab. during increased energy expenditure is significantly increased (≈40%, P < 0.01) in liver of SCD1 knockout mice (SCD1-/-). In parallel with the activation of AMPK, the phosphorylation of acetyl-CoA carboxylase at Ser-79 was increased and enzymic activity was decreased (≈35%, P < 0.001), resulting in decreased intracellular levels of malonyl-CoA (≈47%, P < 0.001). An SCD1 mutation also increased AMPK phosphorylation and activity and increased acetyl-CoA carboxylase phosphorylation in leptin-deficient ob/ob mice. Lower malonyl-CoA concns. are known to derepress carnitine palmitoyltransferase 1 (CPT1). In SCD1-/- mice, CPT1 and CPT2 activities were significantly increased (in both cases ≈60%, P < 0.001) thereby stimulating the oxidn. of mitochondrial palmitoyl-CoA. Our results identify AMPK as a mediator of increased fatty acid oxidn. in liver of SCD1-deficient mice.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXjvVyit7g%253D&md5=a9eb246af096c1443da249b945ded40c

     
288. 288

     Miyazaki, M.; Flowers, M. T.; Sampath, H.; Chu, K.; Otzelberger, C.; Liu, X.; Ntambi, J. M. Hepatic Stearoyl-CoA Desaturase-1 Deficiency Protects Mice from Carbohydrate-Induced Adiposity and Hepatic Steatosis. Cell Metab. 2007, 6, 484– 496,  DOI: 10.1016/j.cmet.2007.10.014

     [Crossref], [PubMed], [CAS], Google Scholar

     288

     Hepatic stearoyl-CoA desaturase-1 deficiency protects mice from carbohydrate-induced adiposity and hepatic steatosis

     Miyazaki, Makoto; Flowers, Matthew T.; Sampath, Harini; Chu, Kiki; Otzelberger, Carolin; Liu, Xueqing; Ntambi, James M.

     Cell Metabolism (2007), 6 (6), 484-496CODEN: CMEEB5; ISSN:1550-4131. (Cell Press)

     Stearoyl-CoA desaturase-1 (SCD1), a crit. regulator of energy metab., catalyzes the synthesis of monounsatd. fats. To understand the tissue-specific role of SCD1 in energy homeostasis, we used Cre-Iox technol. to generate mice with a liver-specific knockout of Scd1 (LKO). LKO mice were protected from high-carbohydrate, but not high-fat (HF), diet-induced adiposity and hepatic steatosis. Addnl., on a high-sucrose, very low-fat (HSVLF) diet, lipogenesis and levels of nuclear SREBP-1 and ChREBP were significantly decreased in the livers of LKO relative to Scd1lox/lox (Lox) mice. HSVLF feeding in LKO mice caused hypoglycemia and hepatic carbohydrate redn. due to an impairment of gluconeogenesis. Oleate, but not sterate, supplementation normalized adiposity, gluconeogenesis, triglyceride secretion, and hepatic lipogenesis of LKO mice. These results indicate that hepatic SCD1 expression (and thus, oleate) is required for carbohydrate-induced adiposity, but SCD1 inhibition in extrahepatic tissues is required to protect mice from HF-induced obesity and insulin resistance.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhsVektb%252FL&md5=b72dd6c635ca9cf4ae3892dda78b6c7c

     
289. 289

     Ratziu, V.; Guevara, L. d.; Safadi, R.; Poordad, F.; Fuster, F.; Flores-Figueroa, J.; Harrison, S. A.; Arrese, M.; Fargion, S.; Bashat, D. B.; Lackner, C.; Gorfine, T.; Kadosh, S.; Oren, R.; Loomba, R.; Sanyal, A. J. One-Year Results of the Global Phase 2b Randomized Placebo Controlled Arrest Trial of Aramchol, a Stearoyl CoA Desaturase Modulator in NASH Patients. Presented at the American Association for the Study of Liver Diseases, San Francisco, USA, November 9–13, 2018; LB-5.

     Google Scholar

     There is no corresponding record for this reference.

     
290. 290

     Bunkoczi, G.; Salah, E.; Filippakopoulos, P.; Fedorov, O.; Muller, S.; Sobott, F.; Parker, S. A.; Zhang, H.; Min, W.; Turk, B. E.; Knapp, S. Structural and Functional Characterization of the Human Protein Kinase ASK1. Structure 2007, 15, 1215– 1226,  DOI: 10.1016/j.str.2007.08.011

     [Crossref], [PubMed], [CAS], Google Scholar

     290

     Structural and Functional Characterization of the Human Protein Kinase ASK1

     Bunkoczi, Gabor; Salah, Eidarus; Filippakopoulos, Panagis; Fedorov, Oleg; Mueller, Susanne; Sobott, Frank; Parker, Sirlester A.; Zhang, Haifeng; Wang, Min; Turk, Benjamin E.; Knapp, Stefan

     Structure (Cambridge, MA, United States) (2007), 15 (10), 1215-1226CODEN: STRUE6; ISSN:0969-2126. (Cell Press)

     Apoptosis signal-regulating kinase 1 (ASK1) plays an essential role in stress and immune response and has been linked to the development of several diseases. Here, we present the structure of the human ASK1 catalytic domain in complex with staurosporine. Anal. ultracentrifugation (AUC) and crystallog. anal. showed that ASK1 forms a tight dimer (Kd ∼ 0.2 μM) interacting in a head-to-tail fashion. We found that the ASK1 phosphorylation motifs differ from known ASK1 phosphorylation sites but correspond well to autophosphorylation sites identified by mass spectrometry. Reporter gene assays showed that all three identified in vitro autophosphorylation sites (Thr813, Thr838, Thr842) regulate ASK1 signaling, but site-directed mutants showed catalytic activities similar to wild-type ASK1, suggesting a regulatory mechanism independent of ASK1 kinase activity. The detd. high-resoln. structure of ASK1 and identified ATP mimetic inhibitors will provide a first starting point for the further development of selective inhibitors.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhtFKhsLzM&md5=d005be68398be830550509044a54b8f3

     
291. 291

     Fujino, G.; Noguchi, T.; Matsuzawa, A.; Yamauchi, S.; Saitoh, M.; Takeda, K.; Ichijo, H. Thioredoxin and TRAF Family Proteins Regulate Reactive Oxygen Species-Dependent Activation of ASK1 Through Reciprocal Modulation of the N-Terminal Homophilic Interaction of ASK1. Mol. Cell. Biol. 2007, 27, 8152– 8163,  DOI: 10.1128/MCB.00227-07

     [Crossref], [PubMed], [CAS], Google Scholar

     291

     Thioredoxin and TRAF family proteins regulate reactive oxygen species-dependent activation of ASK1 through reciprocal modulation of the N-terminal homophilic interaction of ASK1

     Fujino, Go; Noguchi, Takuya; Matsuzawa, Atsushi; Yamauchi, Shota; Saitoh, Masao; Takeda, Kohsuke; Ichijo, Hidenori

     Molecular and Cellular Biology (2007), 27 (23), 8152-8163CODEN: MCEBD4; ISSN:0270-7306. (American Society for Microbiology)

     Apoptosis signal-regulating kinase 1 (ASK1), a member of the mitogen-activated protein kinase kinase kinase family, plays pivotal roles in reactive oxygen species (ROS)-induced cellular responses. In resting cells, endogenous ASK1 constitutively forms a homo-oligomerized but still inactive high-mol.-mass complex including thioredoxin (Trx), which we designated the ASK1 signalosome. Upon ROS stimulation, the ASK1 signalosome unbinds from Trx and forms a fully activated higher-mol.-mass complex, in part by recruitment of tumor necrosis factor receptor-assocd. factor 2 (TRAF2) and TRAF6. However, the precise mechanisms by which Trx inhibits and TRAF2 and TRAF6 activate ASK1 have not been elucidated fully. Here we demonstrate that the N-terminal homophilic interaction of ASK1 through the N-terminal coiled-coil domain is required for ROS-dependent activation of ASK1. Trx inhibited this interaction of ASK1, which was, however, enhanced by expression of TRAF2 or TRAF6 or by treatment of cells with H2O2. Furthermore, the H2O2-induced interaction was reduced by double knockdown of TRAF2 and TRAF6. These findings demonstrate that Trx, TRAF2, and TRAF6 regulate ASK1 activity by modulating N-terminal homophilic interaction of ASK1.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhsVeis7fP&md5=0dca18a376c8e8df5739bc3dd5dafbb8

     
292. 292

     Sturchler, E.; Feurstein, D.; McDonald, P.; Duckett, D. Mechanism of Oxidative Stress-Induced ASK1-Catalyzed MKK6 Phosphorylation. Biochemistry 2010, 49, 4094– 4102,  DOI: 10.1021/bi100010j

     [ACS Full Text ], [CAS], Google Scholar

     292

     Mechanism of Oxidative Stress-Induced ASK1-Catalyzed MKK6 Phosphorylation

     Sturchler, Emmanuel; Feurstein, Daniel; McDonald, Patricia; Duckett, Derek

     Biochemistry (2010), 49 (19), 4094-4102CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)

     Apoptosis signal-regulating kinase 1 (ASK1) is a serine/threonine kinase that responds to a plethora of stress-inducing signals. In turn, activation of ASK1 is assocd. with a no. of human pathol. conditions, including neurodegenerative disease, inflammation, and heart failure. In response to oxidative stress, ASK1 activates the cell death-assocd. p38 MAPK pathway by phosphorylating MKK6. Here, we investigated the regulation of oxidative stress-induced ASK1-catalyzed phosphorylation of MKK6. MKK6 phosphorylation levels increased immediately after H2O2 treatment in intact cells and decreased following treatment for 30 min. When expressed in HEK293T cells, ASK1 was reproducibly purified within a high-mol. mass complex (∼1500 kDa) known as the ASK1 signalosome. Measurement of the in vitro kinetic parameters revealed that the catalytic efficiency (kcat/Km) of ASK1 was 4000-fold greater in cells treated with H2O2 for 3 min than in untreated cells. Interestingly, although the Km(ATP) values were found to be unchanged, the Km(MKK6) was dramatically decreased (∼1000-fold). The increased affinity was specific for MKK6 and short-lived, as the Km(MKK6) returned to basal levels 30 min after treatment. Consistently, endogenous MKK6 was found within the ASK1 signalosome in intact cells and in addn. copurified with ASK1 following treatment for 3 min. In contrast, proteins modulating ASK1 activity and degrdn. were found to interact with the ASK1 signalosome once MKK6 activation was completed. Taken together, these data suggest that oxidative stress rapidly increases ASK1 catalytic efficiency for MKK6 phosphorylation by increasing MKK6 binding affinity within the ASK1 signalosome prior to induction of inactivation and degrdn. of the complex.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXltFyrt7o%253D&md5=32ed9f03db3564f18ee4e7169e48252f

     
293. 293

     Weijman, J. F.; Kumar, A.; Jamieson, S. A.; King, C. M.; Caradoc-Davies, T. T.; Ledgerwood, E. C.; Murphy, J. M.; Mace, P. D. Structural Basis of Autoregulatory Scaffolding by Apoptosis Signal-Regulating Kinase 1. Proc. Natl. Acad. Sci. U. S. A. 2017, 114, E2096– E2105,  DOI: 10.1073/pnas.1620813114

     [Crossref], [PubMed], [CAS], Google Scholar

     293

     Structural basis of autoregulatory scaffolding by apoptosis signal-regulating kinase 1

     Weijman, Johannes F.; Kumar, Abhishek; Jamieson, Sam A.; King, Chontelle M.; Caradoc-Davies, Tom T.; Ledgerwood, Elizabeth C.; Murphy, James M.; Mace, Peter D.

     Proceedings of the National Academy of Sciences of the United States of America (2017), 114 (11), E2096-E2105CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)

     Apoptosis signal-regulating kinases (ASK1-3) are apical kinases of the p38 and JNK MAP kinase pathways. They are activated by diverse stress stimuli, including reactive oxygen species, cytokines, and osmotic stress; however, a mol. understanding of how ASK proteins are controlled remains obscure. Here, we report a biochem. anal. of the ASK1 kinase domain in conjunction with its N-terminal thioredoxin-binding domain, along with a central regulatory region that links the 2. We show that in soln. the central regulatory region mediates a compact arrangement of the kinase and thioredoxin-binding domains and the central regulatory region actively primes MKK6, a key ASK1 substrate, for phosphorylation. The crystal structure of the central regulatory region revealed an unusually compact tetratricopeptide repeat (TPR) region capped by a cryptic pleckstrin homol. domain (PHD). Biochem. assays showed that both a conserved surface on the PHD and an intact TPR region were required for ASK1 activity. We propose a model in which the central regulatory region promotes ASK1 activity via its PHD, but also facilitates ASK1 autoinhibition by bringing the thioredoxin-binding and kinase domains into close proximity. Such an architecture provides a mechanism for control of ASK-type kinases by diverse activators and inhibitors and demonstrates an unexpected level of autoregulatory scaffolding in mammalian stress-activated MAP kinase signaling.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXjsVSlsbY%253D&md5=3bb6ae185ec59893170b8ce5da951a5f

     
294. 294

     Volynets, G. P.; Chekanov, M. O.; Synyugin, A. R.; Golub, A. G.; Kukharenko, O. P.; Bdzhola, V. G.; Yarmoluk, S. M. Identification of 3H-Naphtho[1,2,3-de]quinoline-2,7-diones as Inhibitors of Apoptosis Signal-Regulating Kinase 1 (ASK1). J. Med. Chem. 2011, 54, 2680– 2686,  DOI: 10.1021/jm200117h

     [ACS Full Text ], [CAS], Google Scholar

     294

     Identification of 3H-Naphtho[1,2,3-de]quinoline-2,7-diones as Inhibitors of Apoptosis Signal-Regulating Kinase 1 (ASK1)

     Volynets, Galyna P.; Chekanov, Maksym O.; Synyugin, Anatoliy R.; Golub, Andriy G.; Kukharenko, Oleksandr P.; Bdzhola, Volodymyr G.; Yarmoluk, Sergiy M.

     Journal of Medicinal Chemistry (2011), 54 (8), 2680-2686CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

     Apoptosis signal-regulating kinase 1 (ASK1) has recently emerged as an attractive therapeutic target for the treatment of cardiac and neurodegenerative disorders. The selective inhibitors of ASK1 may become important compds. for the development of clin. agents. We have identified the ASK1 inhibitor among 3H-naphtho[1,2,3-de]quinoline-2,7-diones using receptor-based virtual screening. In vitro kinase assay revealed that Et 2,7-dioxo-2,7-dihydro-3H-naphtho[1,2,3-de]quinoline-1-carboxylate (NQDI-1) inhibited ASK1 with a Ki of 500 nM. The competitive character of inhibition is demonstrated in Lineweaver-Burk plots. In our preliminary selectivity study this compd. exhibited strong specific inhibitory activity toward ASK1.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXktVCnsL4%253D&md5=21bd432815a6e38306ce0ea2d20b5fa6

     
295. 295

     Volynets, G. P.; Bdzhola, V. G.; Golub, A. G.; Synyugin, A. R.; Chekanov, M. A.; Kukharenko, O. P.; Yarmoluk, S. M. Rational Design of Apoptosis Signal-Regulating Kinase 1 Inhibitors: Discovering Novel Structural Scaffold. Eur. J. Med. Chem. 2013, 61, 104– 115,  DOI: 10.1016/j.ejmech.2012.09.022

     [Crossref], [PubMed], [CAS], Google Scholar

     295

     Rational design of apoptosis signal-regulating kinase 1 inhibitors: Discovering novel structural scaffold

     Volynets, Galyna P.; Bdzhola, Volodymyr G.; Golub, Andriy G.; Synyugin, Anatoliy R.; Chekanov, Maksym A.; Kukharenko, Oleksandr P.; Yarmoluk, Sergiy M.

     European Journal of Medicinal Chemistry (2013), 61 (), 104-115CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)

     Increased activity of apoptosis signal-regulating kinase 1 (ASK1) is assocd. with a no. of human disorders and the inhibitors of ASK1 may become important compds. for pharmaceutical application. Here we report novel ASK1 inhibitor scaffold, namely 5-(5-Phenyl-furan-2-ylmethylene)-2-thioxo-thiazolidin-4-one, that has been identified using virtual screening and biochem. tests. A series of derivs. has been synthesized and evaluated in vitro towards human protein kinase ASK1. It was revealed that the most active compds. 4-((5Z)-5-{[5-(4-bromophenyl)-2-furyl]methylene}-4-oxo-2-thioxo-1,3-thiazolidin-3-yl)butanoic acid and 6-((5Z)-5-{[5-(4-bromophenyl)-2-furyl]methylene}-4-oxo-2-thioxo-1,3-thiazolidin-3-yl)hexanoic acid inhibit ASK1 with IC50 of 0.2 μM. Structure-activity relationships of 33 derivs. of 5-(5-Phenyl-furan-2-ylmethylene)-2-thioxo-thiazolidin-4-one have been studied and binding mode of this chem. class has been predicted.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsVKksbbJ&md5=089632522c3211b3680bf585919f67a4

     
296. 296

     Terao, Y.; Suzuki, H.; Yoshikawa, M.; Yashiro, H.; Takekawa, S.; Fujitani, Y.; Okada, K.; Inoue, Y.; Yamamoto, Y.; Nakagawa, H.; Yao, S.; Kawamoto, T.; Uchikawa, O. Design and Biological Evaluation of Imidazo[1,2-a]pyridines as Novel and Potent ASK1 Inhibitors. Bioorg. Med. Chem. Lett. 2012, 22, 7326– 7329,  DOI: 10.1016/j.bmcl.2012.10.084

     [Crossref], [PubMed], [CAS], Google Scholar

     296

     Design and biological evaluation of imidazo[1,2-a]pyridines as novel and potent ASK1 inhibitors

     Terao, Yoshito; Suzuki, Hideo; Yoshikawa, Masato; Yashiro, Hiroaki; Takekawa, Shiro; Fujitani, Yasushi; Okada, Kengo; Inoue, Yoshihisa; Yamamoto, Yoshio; Nakagawa, Hideyuki; Yao, Shuhei; Kawamoto, Tomohiro; Uchikawa, Osamu

     Bioorganic & Medicinal Chemistry Letters (2012), 22 (24), 7326-7329CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)

     Imidazo[1,2-a]pyridine derivs. were designed, synthesized, and evaluated as inhibitors of the apoptosis signal-regulating kinase 1 (ASK1). These were based on a benzothiazole deriv. that was discovered from high-throughput screening of our compd. library. As a result, we identified potent, selective, and orally bioavailable ASK1 inhibitors for wide range of therapeutic targets.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xhs1KjsLfL&md5=0f9e77840d3d18377bb97a12fe82c593

     
297. 297

     Singh, O.; Shillings, A.; Craggs, P.; Wall, I.; Rowland, P.; Skarzynski, T.; Hobbs, C. I.; Hardwick, P.; Tanner, R.; Blunt, M.; Witty, D. R.; Smith, K. J. Crystal Structures of ASK1-Inhibtor Complexes Provide a Platform for Structure-Based Drug Design. Protein Sci. 2013, 22, 1071– 1077,  DOI: 10.1002/pro.2298

     [Crossref], [PubMed], [CAS], Google Scholar

     297

     Crystal structures of ASK1-inhibitor complexes provide a platform for structure-based drug design

     Singh, Onkar; Shillings, Anthony; Craggs, Peter; Wall, Ian; Rowland, Paul; Skarzynski, Tadeusz; Hobbs, Clare I.; Hardwick, Phil; Tanner, Rob; Blunt, Michelle; Witty, David R.; Smith, Kathrine J.

     Protein Science (2013), 22 (8), 1071-1077CODEN: PRCIEI; ISSN:1469-896X. (Wiley-Blackwell)

     ASK1, a member of the MAPK kinase kinase family of proteins has been shown to play a key role in cancer, neurodegeneration and cardiovascular diseases and is emerging as a possible drug target. Here we describe a 'replacement-soaking' method that has enabled the high-throughput X-ray structure detn. of ASK1/ligand complexes. Comparison of the X-ray structures of five ASK1/ligand complexes from 3 different chemotypes illustrates that the ASK1 ATP binding site is able to accommodate a range of chem. diversity and different binding modes. The replacement-soaking system is also able to tolerate some protein flexibility. This crystal system provides a robust platform for ASK1/ligand structure detn. and future structure based drug design.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtFOis7fJ&md5=0f0ccc790c7165096b3c37cf26426ce3

     
298. 298

     Budas, G. K. S.; Jonnson, T.; Shafizadeh, T.; Watkins, S.; Breckenridge, D.; Tumas, D. Reduction of Liver Steatosis and Fibrosis with an ASK1 Inhibitor in a Murine Model of Nash is Accompanied by Improvements in Cholesterol, Bile Acid and Lipid Metabolism. Presented at the European Associate for the Study of the Liver International Liver Conference, Barcelona, Spain, April 13–17, 2016; PS070.

     Google Scholar

     There is no corresponding record for this reference.

     
299. 299

     Notte, G. Apoptosis Signal-Regulating Kinase Inhibitor. International Patent WO2013112741, 2013.

     Google Scholar

     There is no corresponding record for this reference.

     
300. 300

     Lanier, M.; Pickens, J.; Bigi, S. V.; Bradshaw-Pierce, E. L.; Chambers, A.; Cheruvallath, Z. S.; Cole, D.; Dougan, D. R.; Ermolieff, J.; Gibson, T.; Halkowycz, P.; Hirokawa, A.; Ivetac, A.; Miura, J.; Nunez, E.; Sabat, M.; Tyhonas, J.; Wang, H.; Wang, X.; Swann, S. Structure-Based Design of ASK1 Inhibitors as Potential Agents for Heart Failure. ACS Med. Chem. Lett. 2017, 8, 316– 320,  DOI: 10.1021/acsmedchemlett.6b00481

     [ACS Full Text ], [CAS], Google Scholar

     300

     Structure-Based Design of ASK1 Inhibitors as Potential Agents for Heart Failure

     Lanier, Marion; Pickens, Jason; Bigi, Simone V.; Bradshaw-Pierce, Erica L.; Chambers, Alison; Cole, Derek; Dougan, Douglas R.; Ermolieff, Jacques; Gibson, Tony; Halkowycz, Petro; Hirokawa, Aki; Ivetac, Anthony; Miura, Joanne; Nunez, Evan; Sabat, Mark; Tyhonas, John; Wang, Haixia; Wang, Xiaolun; Swann, Steve

     ACS Medicinal Chemistry Letters (2017), 8 (3), 316-320CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)

     Apoptosis signal-regulating kinase 1 (ASK1/MAP3K) is a mitogen-activated protein kinase family member shown to contribute to acute ischemia/reperfusion injury. Using structure-based drug design, deconstruction, and reoptimization of a known ASK1 inhibitor, a lead compd. was identified. This compd. displayed robust MAP3K pathway inhibition and redn. of infarct size in an isolated perfused heart model of cardiac injury.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXisVSqt7Y%253D&md5=f6118d66141ad3479dbb80c582819306

     
301. 301

     Liles, J. T.; Corkey, B. K.; Notte, G. T.; Budas, G. R.; Lansdon, E. B.; Hinojosa-Kirschenbaum, F.; Badal, S. S.; Lee, M.; Schultz, B. E.; Wise, S.; Pendem, S.; Graupe, M.; Castonguay, L.; Koch, K. A.; Wong, M. H.; Papalia, G. A.; French, D. M.; Sullivan, T.; Huntzicker, E. G.; Ma, F. Y.; Nikolic-Paterson, D. J.; Altuhaifi, T.; Yang, H.; Fogo, A. B.; Breckenridge, D. G. ASK1 Contributes to Fibrosis and Dysfunction in Models of Kidney Disease. J. Clin. Invest. 2018, 128, 4485– 4500,  DOI: 10.1172/JCI99768

     [Crossref], [PubMed], [CAS], Google Scholar

     301

     ASK1 contributes to fibrosis and dysfunction in models of kidney disease

     Liles John T; Corkey Britton K; Notte Gregory T; Budas Grant R; Lansdon Eric B; Hinojosa-Kirschenbaum Ford; Badal Shawn S; Lee Michael; Schultz Brian E; Wise Sarah; Pendem Swetha; Graupe Michael; Wong Melanie H; Papalia Giuseppe A; French Dorothy M; Sullivan Theodore; Huntzicker Erik G; Breckenridge David G; Castonguay Laurie; Koch Keith A; Ma Frank Y; Nikolic-Paterson David J; Altuhaifi Tareq; Yang Haichun; Fogo Agnes B

     The Journal of clinical investigation (2018), 128 (10), 4485-4500 ISSN:.

     Oxidative stress is an underlying component of acute and chronic kidney disease. Apoptosis signal-regulating kinase 1 (ASK1) is a widely expressed redox-sensitive serine threonine kinase that activates p38 and c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase kinases, and induces apoptotic, inflammatory, and fibrotic signaling in settings of oxidative stress. We describe the discovery and characterization of a potent and selective small-molecule inhibitor of ASK1, GS-444217, and demonstrate the therapeutic potential of ASK1 inhibition to reduce kidney injury and fibrosis. Activation of the ASK1 pathway in glomerular and tubular compartments was confirmed in renal biopsies from patients with diabetic kidney disease (DKD) and was decreased by GS-444217 in several rodent models of kidney injury and fibrosis that collectively represented the hallmarks of DKD pathology. Treatment with GS-444217 reduced progressive inflammation and fibrosis in the kidney and halted glomerular filtration rate decline. Combination of GS-444217 with enalapril, an angiotensin-converting enzyme inhibitor, led to a greater reduction in proteinuria and regression of glomerulosclerosis. These results identify ASK1 as an important target for renal disease and support the clinical development of an ASK1 inhibitor for the treatment of DKD.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3c%252FpvVGisw%253D%253D&md5=088f51fa49e871d1123a51d2331c2144

     
302. 302

     Loomba, R.; Lawitz, E.; Mantry, P. S.; Jayakumar, S.; Caldwell, S. H.; Arnold, H.; Diehl, A. M.; Djedjos, C. S.; Han, L.; Myers, R. P.; Subramanian, G. M.; McHutchison, J. G.; Goodman, Z. D.; Afdhal, N. H.; Charlton, M. R. The ASK1 Inhibitor Selonsertib in Patients with Nonalcoholic Steatohepatitis: A Randomized, Phase 2 Trial. Hepatology 2018, 67, 549– 559,  DOI: 10.1002/hep.29514

     [Crossref], [PubMed], [CAS], Google Scholar

     302

     The ASK1 inhibitor selonsertib in patients with nonalcoholic steatohepatitis: A randomized, phase 2 trial

     Loomba, Rohit; Lawitz, Eric; Mantry, Parvez S.; Jayakumar, Saumya; Caldwell, Stephen H.; Arnold, Hays; Diehl, Anna Mae; Djedjos, C. Stephen; Han, Ling; Myers, Robert P.; Subramanian, G. Mani; McHutchison, John G.; Goodman, Zachary D.; Afdhal, Nezam H.; Charlton, Michael R.

     Hepatology (Hoboken, NJ, United States) (2018), 67 (2), 549-559CODEN: HPTLD9; ISSN:0270-9139. (John Wiley & Sons, Inc.)

     Inhibition of apoptosis signal-regulating kinase 1, a serine/threonine kinase, leads to improvement in inflammation and fibrosis in animal models of nonalcoholic steatohepatitis. We evaluated the safety and efficacy of selonsertib, a selective inhibitor of apoptosis signal-regulating kinase 1, alone or in combination with simtuzumab, in patients with nonalcoholic steatohepatitis and stage 2 or 3 liver fibrosis. In this multicenter phase 2 trial, 72 patients were randomized to receive 24 wk of open-label treatment with either 6 or 18 mg of selonsertib orally once daily with or without once-weekly injections of 125 mg of simtuzumab or simtuzumab alone. The effect of treatment was assessed by paired pretreatment and posttreatment liver biopsies, magnetic resonance elastog., magnetic resonance imaging-estd. proton d. fat fraction, quant. collagen content, and noninvasive markers of liver injury. Due to the lack of effect of simtuzumab on histol. or selonsertib pharmacokinetics, selonsertib groups with and without simtuzumab were pooled. After 24 wk of treatment, the proportion of patients with a one or more stage redn. in fibrosis in the 18-mg selonsertib group was 13 of 30 (43%; 95% confidence interval, 26-63); in the 6-mg selonsertib group, 8 of 27 (30%; 95% confidence interval, 14-50); and in the simtuzumab-alone group, 2 of 10 (20%; 95% confidence interval, 3-56). Improvement in fibrosis was assocd. with redns. in liver stiffness on magnetic resonance elastog., collagen content and lobular inflammation on liver biopsy, as well as improvements in serum biomarkers of apoptosis and necrosis. There were no significant differences in adverse events between the treatment groups. Conclusion: These findings suggest that selonsertib may reduce liver fibrosis in patients with nonalcoholic steatohepatitis and stage 2-3 fibrosis. (Hepatol. 2018;67:549-559).

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhsFKjtbs%253D&md5=ca04f9bbc0b7d65c2b4493d479c2d751

     
303. 303

     Lawitz, E.; Herring, R.; Younes, Z. H.; Gane, E.; Ruane, P. J.; Aguilar, R.; Jia, C.; Xu, R.; McColgan, B.; Djedjos, C. S.; Subramanian, G. M.; McHutchison, J. G.; Myers, R. P.; Middleton, M.; Li, K.; Hellerstein, M.; Kwo, P.; Noureddin, M.; Harrison, S. A. Proof-of-Concept Study of an Apoptosis-Signal Regulating Kinase (ASK1) Inhibitor (Selonsertib) in Combination with an Acetyl-CoA Carboxylase Inhibitor (GS-0976) or a Farnesoid X Receptor (FXR) Agonist (GS-9674) in NASH. Presented at the European Association for the Study of the Liver International Liver Conference, Paris, France, April 11–15, 2018; PS-105.

     Google Scholar

     There is no corresponding record for this reference.

     
304. 304

     Gilead https://www.gilead.com/news-and-press/press-room/press-releases/2019/12/gilead-announces-topline-results-from-phase-2-atlas-study-in-patients-with-bridging-fibrosis-f3-and-compensated-cirrhosis-f4-due-to-nonalcoholic-s (accessed Dec 18, 2019).

     Google Scholar

     There is no corresponding record for this reference.

     
305. 305

     Galluzzi, L.; Lopez-Soto, A.; Kumar, S.; Kroemer, G. Caspases Connect Cell-Death Signaling to Organismal Homeostasis. Immunity 2016, 44, 221– 231,  DOI: 10.1016/j.immuni.2016.01.020

     [Crossref], [PubMed], [CAS], Google Scholar

     305

     Caspases Connect Cell-Death Signaling to Organismal Homeostasis

     Galluzzi, Lorenzo; Lopez-Soto, Alejandro; Kumar, Sharad; Kroemer, Guido

     Immunity (2016), 44 (2), 221-231CODEN: IUNIEH; ISSN:1074-7613. (Elsevier Inc.)

     Some forms of regulated cell death, such as apoptosis, are pptd. by the activation of cysteine proteases of the caspase family, including caspase 8, 9, and 3. Other caspases, such as caspase 1 and 4, are well known for their pro-inflammatory functions but regulate cell death in a limited no. of pathophysiol. settings. Accumulating evidence suggests that the most conserved function of mammalian caspases is not to control cell death sensu stricto, but to regulate inflammatory and immune reactions to dying cells and infectious challenges. Here, we review the mol. and cellular mechanisms though which mammalian caspases connect cell-death signaling to the maintenance of organismal homeostasis.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XjtVCmsLw%253D&md5=188e1335c0068bb3bc972ce9e1487332

     
306. 306

     Earnshaw, W. C.; Martins, L. M.; Kaufmann, S. H. Mammalian Caspases: Structure, Activation, Substrates, and Functions During Apoptosis. Annu. Rev. Biochem. 1999, 68, 383– 424,  DOI: 10.1146/annurev.biochem.68.1.383

     [Crossref], [PubMed], [CAS], Google Scholar

     306

     Mammalian caspases: structure, activation, substrates, and functions during apoptosis

     Earnshaw, William C.; Martins, Luis M.; Kaufmann, Scott H.

     Annual Review of Biochemistry (1999), 68 (), 383-424CODEN: ARBOAW; ISSN:0066-4154. (Annual Reviews Inc.)

     A review with 380 refs. Apoptosis is a genetically programmed, morphol. distinct form of cell death that can be triggered by a variety of physiol. and pathol. stimuli. Studies performed over the past 10 yr have demonstrated that proteases play crit. roles in initiation and execution of this process. The caspases, a family of cysteine-dependent aspartate-directed proteases, are prominent among the death proteases. Caspases are synthesized as relatively inactive zymogens that become activated by scaffold-mediated transactivation or by cleavage via upstream proteases in an intracellular cascade. Regulation of caspase activation and activity occurs at several different levels: (1) Zymogen gene transcription is regulated; (2) anti-apoptotic members of the Bcl-2 family and other cellular polypeptides block proximity-induced activation of certain procaspases; and (3) certain cellular inhibitor of apoptosis proteins (cIAPs) can bind to and inhibit active caspases. Once activated, caspases cleave a variety of intracellular polypeptides, including major structural elements of the cytoplasm and nucleus, components of the DNA repair machinery, and a no. of protein kinases. Collectively, these scissions disrupt survival pathways and disassemble important architectural components of the cell, contributing to the stereotypic morphol. and biochem. changes that characterize apoptotic cell death.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXlvFajsb0%253D&md5=f5735debc5de570edb8a396d01394ac0

     
307. 307

     Fuentes-Prior, P.; Salvesen, G. S. The Protein Structures that Shape Caspase Activity, Specificity, Activation and Inhibition. Biochem. J. 2004, 384, 201– 232,  DOI: 10.1042/BJ20041142

     [Crossref], [PubMed], [CAS], Google Scholar

     307

     The protein structures that shape caspase activity, specificity, activation and inhibition

     Fuentes-Prior, Pablo; Salvesen, Guy S.

     Biochemical Journal (2004), 384 (2), 201-232CODEN: BIJOAK; ISSN:0264-6021. (Portland Press Ltd.)

     A review. The death morphol. commonly known as apoptosis results from a post-translational pathway driven largely by specific limited proteolysis. In the last decade the structural basis for apoptosis regulation has moved from nothing to 'quite good', and we now know the fundamental structures of examples from the initiator phase, the pre-mitochondrial regulator phase, the executioner phase, inhibitors and their antagonists, and even the structures of some substrates. The field is as well advanced as the best known of proteolytic pathways, the coagulation cascade. Fundamentally new mechanisms in protease regulation have been disclosed. Structural evidence suggests that caspases have an unusual catalytic mechanism, and that they are activated by apparently unrelated events, depending on which position in the apoptotic pathway they occupy. Some naturally occurring caspase inhibitors have adopted classic inhibition strategies, but other have revealed completely novel mechanisms. All of the structural and mechanistic information can, and is, being applied to drive therapeutic strategies to combat overactivation of apoptosis in degenerative disease, and underactivation in neoplasia. We present a comprehensive review of the caspases, their regulators and inhibitors from a structural and mechanistic point of view, and with an aim to consolidate the many threads that define the rapid growth of this field.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXhtVSqs7rP&md5=b3c9b22933c76e89ee5fa993e9ec2247

     
308. 308

     McBride, C. B.; McPhail, L. T.; Steeves, J. D. Emerging Therapeutic Targets in Caspase-Dependent Disease. Emerging Ther. Targets 1999, 3, 391– 411,  DOI: 10.1517/14728222.3.3.391

     [Crossref], [CAS], Google Scholar

     308

     Emerging therapeutic targets in caspase-dependent disease

     McBride, Christopher B.; McPhail, Lowell T.; Steeves, John D.

     Emerging Therapeutic Targets (1999), 3 (3), 391-411CODEN: ETTAF7; ISSN:1460-0412. (Ashley Publications)

     A review with 189 refs. Caspases are cysteine proteases which serve as the central executioners of apoptotic pathways induced by a wide variety of stimuli. Deregulation of apoptosis and caspase activity contributes to a large no. of pathol. conditions, including neurodegenerative disorders, stroke, autoimmune disease, disorders involving chronic inflammation, and cancer. Thus, caspases are prime targets for therapeutic interventions aimed at treating these conditions. This review will examine the structure and function of caspases and highlight the findings of applications that inhibit or promote caspase activity in animal models in order to illuminate potential avenues for caspase-regulating drug development.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXlvFGmt7s%253D&md5=7ef62e5d9a9d6168a993fcbd1072f572

     
309. 309

     Lemoinne, S.; Thabut, D.; Housset, C.; Moreau, R.; Valla, D.; Boulanger, C. M.; Rautou, P. E. The Emerging Roles of Microvesicles in Liver Diseases. Nat. Rev. Gastroenterol. Hepatol. 2014, 11, 350– 361,  DOI: 10.1038/nrgastro.2014.7

     [Crossref], [PubMed], [CAS], Google Scholar

     309

     The emerging roles of microvesicles in liver diseases

     Lemoinne, Sara; Thabut, Dominique; Housset, Chantal; Moreau, Richard; Valla, Dominique; Boulanger, Chantal M.; Rautou, Pierre-Emmanuel

     Nature Reviews Gastroenterology & Hepatology (2014), 11 (6), 350-361CODEN: NRGHA9; ISSN:1759-5045. (Nature Publishing Group)

     A review. Microvesicles (MVs) are extracellular vesicles released by virtually all cells, under both physiol. and pathol. conditions. They contain lipids, proteins, RNAs and microRNAs and act as vectors of information that regulate the function of target cells. This review provides an overview of the studies assessing circulating MV levels in patients with liver diseases, together with an insight into the mechanisms that could account for these changes. We also present a detailed anal. of the implication of MVs in key processes of liver diseases. MVs have a dual role in fibrosis as certain types of MVs promote fibrolysis by increasing expression of matrix metalloproteinases, whereas others promote fibrosis by stimulating processes such as angiogenesis. MVs probably enhance portal hypertension by contributing to intrahepatic vasoconstriction, splanchnic vasodilation and angiogenesis. As MVs can modulate vascular permeability, vascular tone and angiogenesis, they might contribute to several complications of cirrhosis including hepatic encephalopathy, hepatopulmonary syndrome and hepatorenal syndrome. Several results also suggest that MVs have a role in hepatocellular carcinoma. Although MVs represent promising biomarkers in patients with liver disease, methods of isolation and subsequent anal. must be standardized.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXitFalu7Y%253D&md5=6239a9c80c8865f4b46421b431e17891

     
310. 310

     Linton, S. D. Caspase Inhibitors: A Pharmaceutical Industry Perspective. Curr. Top. Med. Chem. 2005, 5, 1697– 1717,  DOI: 10.2174/156802605775009720

     [Crossref], [PubMed], [CAS], Google Scholar

     310

     Caspase inhibitors: a pharmaceutical industry perspective

     Linton, Steven D.

     Current Topics in Medicinal Chemistry (Sharjah, United Arab Emirates) (2005), 5 (16), 1697-1716CODEN: CTMCCL; ISSN:1568-0266. (Bentham Science Publishers Ltd.)

     A review. Caspase inhibition has been demonstrated to be therapeutically effective in moderating excessive programmed cell death, or apoptosis. Publications detailing programs in the pharmaceutical industry have been more frequent in recent years, ranging from SAR studies to clin. relevant animal models of disease. A summary of the work published in this exciting new area is presented, outlining the broad applicability of this fundamental cellular mechanism across several disease indications. This area of research has matured to the level of advancing compds. into clin. trials: VX-740 (Pralnacasan) and VX-765 as anti-inflammatory agents, and IDN-6556, a pan-caspase inhibitor as an anti-apoptotic agent.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XislSlsb4%253D&md5=90117df2461483c7833cb80f27c4e861

     
311. 311

     Linton, S. D.; Aja, T.; Armstrong, R. A.; Bai, X.; Chen, L. S.; Chen, N.; Ching, B.; Contreras, P.; Diaz, J. L.; Fisher, C. D.; Fritz, L. C.; Gladstone, P.; Groessl, T.; Gu, X.; Herrmann, J.; Hirakawa, B. P.; Hoglen, N. C.; Jahangiri, K. G.; Kalish, V. J.; Karanewsky, D. S.; Kodandapani, L.; Krebs, J.; McQuiston, J.; Meduna, S. P.; Nalley, K.; Robinson, E. D.; Sayers, R. O.; Sebring, K.; Spada, A. P.; Ternansky, R. J.; Tomaselli, K. J.; Ullman, B. R.; Valentino, K. L.; Weeks, S.; Winn, D.; Wu, J. C.; Yeo, P.; Zhang, C. Z. First-In-Class Pan Caspase Inhibitor Developed for the Treatment of Liver Disease. J. Med. Chem. 2005, 48, 6779– 6782,  DOI: 10.1021/jm050307e

     [ACS Full Text ], [CAS], Google Scholar

     311

     First-in-Class Pan Caspase Inhibitor Developed for the Treatment of Liver Disease

     Linton, Steven D.; Aja, Teresa; Armstrong, Robert A.; Bai, Xu; Chen, Long-Shiuh; Chen, Ning; Ching, Brett; Contreras, Patricia; Diaz, Jose-Luis; Fisher, Craig D.; Fritz, Lawrence C.; Gladstone, Patricia; Groessl, Todd; Gu, Xin; Herrmann, Julia; Hirakawa, Brad P.; Hoglen, Niel C.; Jahangiri, Kathy G.; Kalish, Vincent J.; Karanewsky, Donald S.; Kodandapani, Lalitha; Krebs, Joseph; McQuiston, Jeff; Meduna, Steven P.; Nalley, Kip; Robinson, Edward D.; Sayers, Robert O.; Sebring, Kristen; Spada, Alfred P.; Ternansky, Robert J.; Tomaselli, Kevin J.; Ullman, Brett R.; Valentino, Karen L.; Weeks, Suzanne; Winn, David; Wu, Joe C.; Yeo, Pauline; Zhang, Cheng-zhi

     Journal of Medicinal Chemistry (2005), 48 (22), 6779-6782CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

     A series of oxamyl dipeptides were optimized for pan caspase inhibition, antiapoptotic cellular activity and in vivo efficacy. This structure-activity relationship study focused on the P4 oxamides and warhead moieties. Primarily on the basis of in vitro data, inhibitors were selected for study in a murine model of α-Fas-induced liver injury. IDN-6556 (I) was further profiled in addnl. in vivo models and pharmacokinetic studies. This first-in-class caspase inhibitor is now the subject of two Phase II clin. trials, evaluating its safety and efficacy for use in liver disease.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhtVKmtLbO&md5=3799e72b810914e0e055f421a662e7b3

     
312. 312

     Conatus Collaboration https://www.conatuspharma.com/partnerships (accessed Sept 25, 2019).

     Google Scholar

     There is no corresponding record for this reference.

     
313. 313

     Ullman, B. R.; Aja, T.; Deckwerth, T. L.; Diaz, J. L.; Herrmann, J.; Kalish, V. J.; Karanewsky, D. S.; Meduna, S. P.; Nalley, K.; Robinson, E. D.; Roggo, S. P.; Sayers, R. O.; Schmitz, A.; Ternansky, R. J.; Tomaselli, K. J.; Wu, J. C. Structure-Activity Relationships within a Series of Caspase Inhibitors: Effect of Leaving Group Modifications. Bioorg. Med. Chem. Lett. 2003, 13, 3623– 3626,  DOI: 10.1016/S0960-894X(03)00755-8

     [Crossref], [PubMed], [CAS], Google Scholar

     313

     Structure-activity relationships within a series of caspase inhibitors: effect of leaving group modifications

     Ullman, Brett R.; Aja, Teresa; Deckwerth, Thomas L.; Diaz, Jose-Luis; Herrmann, Julia; Kalish, Vincent J.; Karanewsky, Donald S.; Meduna, Steven P.; Nalley, Kip; Robinson, Edward D.; Roggo, Silvio P.; Sayers, Robert O.; Schmitz, Albert; Ternansky, Robert J.; Tomaselli, Kevin J.; Wu, Joe C.

     Bioorganic & Medicinal Chemistry Letters (2003), 13 (20), 3623-3626CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science B.V.)

     Various aryloxymethyl ketones having the 1-naphthyloxyacetyl-Val-Asp backbone have been prepd. A systematic study of their structure-activity relationship (SAR) related to caspases 1, 3, 6, and 8 is reported. Highly potent irreversible broad-spectrum caspase inhibitors have been identified and their efficacy in cellular models of cell death and inflammation are discussed.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXnsVKgtLo%253D&md5=b83ada6991bbf3165c044b2a77f2f1be

     
314. 314

     Barreyro, F. J.; Holod, S.; Finocchietto, P. V.; Camino, A. M.; Aquino, J. B.; Avagnina, A.; Carreras, M. C.; Poderoso, J. J.; Gores, G. J. The Pan-Caspase Inhibitor Emricasan (IDN-6556) Decreases Liver Injury and Fibrosis in a Murine Model of Non-Alcoholic Steatohepatitis. Liver Int. 2015, 35, 953– 966,  DOI: 10.1111/liv.12570

     [Crossref], [PubMed], [CAS], Google Scholar

     314

     The pan-caspase inhibitor Emricasan (IDN-6556) decreases liver injury and fibrosis in a murine model of non-alcoholic steatohepatitis

     Barreyro, Fernando J.; Holod, Silvia; Finocchietto, Paola V.; Camino, Alejandra M.; Aquino, Jorge B.; Avagnina, Alejandra; Carreras, Maria C.; Poderoso, Juan J.; Gores, Gregory J.

     Liver International (2015), 35 (3), 953-966CODEN: LIINCM; ISSN:1478-3223. (Wiley-Blackwell)

     Background & Aims : Hepatocyte apoptosis, the hallmark of non-alc. steatohepatitis (NASH) contributes to liver injury and fibrosis. Although, both the intrinsic and extrinsic apoptotic pathways are involved in the pathogenesis of NASH, the final common step of apoptosis is executed by a family of cysteine-proteases termed caspases. Thus, our aim was to ascertain if administration of Emricasan, a pan-caspase inhibitor, ameliorates liver injury and fibrosis in a murine model of NASH. Methods : C57/BL6J-mice were fed regular chow or high fat diet (HFD) for 20 wk. All mice were treated with vehicle or Emricasan. Results : Mice fed a HFD diet demonstrate a five-fold increase in hepatocyte apoptosis by the TUNEL assay and a 1.5-fold and 1.3-fold increase in caspase-3 and-8 activities resp.; this increase in apoptosis was substantially attenuated in mice fed a HFD treated with Emricasan (HFD-Em). Likewise, liver injury and inflammation were reduced in mice fed HFD-Em as compare to HFD by measuring serum aspartate aminotransferase and alanine aminotransferase levels, NAS histol. score and IL 1-β, TNF-α, monocyte chemoattractant protein (MCP-1) and C-X-C chemokine ligand-2 (CXCL2) quant. reverse-transcription polymerase chain reaction (qPCR). These differences could not be attributed to differences in hepatic steatosis as liver triglycerides content were similar in both HFD groups. Hepatic fibrosis was reduced by Emricasan in HFD animals by decreasing αSMA (a marker for hepatic stellate cell activation), fibrosis score, Sirius red staining, hydroxyproline liver content and profibrogenic cytokines by qPCR. Conclusion : In conclusion, these data demonstrate that in a murine model of NASH, liver injury and fibrosis are suppressed by inhibiting hepatocytes apoptosis and suggests that Emricasan may be an attractive antifibrotic therapy in NASH.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXivVehsbg%253D&md5=7c88cb738e13e08badf46416bb9340c6

     
315. 315

     Harrison, S. A.; Goodman, Z. D.; Jabbar, A.; Younes, Z.; Vemulapalli, R.; Freilich, B. L.; Sheikh, M. Y.; Schattenberg, J.; Kayali, Z.; Zivony, A. S.; Sheikh, A. M.; Garcia-Samaniego, J.; Satapathy, S. K.; Therapondos, G.; Mena, E. A.; Schuppan, D.; Robinson, J. M.; Chan, J. L.; Hagerty, D.; Sanyal, A. J. A Multicenter, Double-Blind, Placebo-Controlled, Randomized Trial of Emricasan in Subjects with Nonalcoholic Steatohepatitis (NASH) and Fibrosis. Presented at the European Associate for the Study of the Liver International Liver Conference, Vienna, Austria, April 10–14, 2019; 61.

     Google Scholar

     There is no corresponding record for this reference.

     
316. 316

     Conatus https://www.globenewswire.com/news-release/2019/06/24/1873299/0/en/Conatus-Announces-Results-from-ENCORE-LF-and-ENCORE-PH-Phase-2b-Clinical-Trials-in-NASH-Cirrhosis.html (accessed Sept 25, 2019).

     Google Scholar

     There is no corresponding record for this reference.

     
317. 317

     Marra, F.; Tacke, F. Roles for Chemokines in Liver Disease. Gastroenterology 2014, 147, 577– 594,  DOI: 10.1053/j.gastro.2014.06.043

     [Crossref], [PubMed], [CAS], Google Scholar

     317

     Roles for Chemokines in Liver Disease

     Marra, Fabio; Tacke, Frank

     Gastroenterology (2014), 147 (3), 577-594.e1CODEN: GASTAB; ISSN:0016-5085. (Elsevier)

     A review. Sustained hepatic inflammation is an important factor in progression of chronic liver diseases, including hepatitis C or non-alc. steatohepatitis. Liver inflammation is regulated by chemokines, which regulate the migration and activities of hepatocytes, Kupffer cells, hepatic stellate cells, endothelial cells, and circulating immune cells. However, the effects of the different chemokines and their receptors vary during pathogenesis of different liver diseases. During development of chronic viral hepatitis, CCL5 and CXCL10 regulate the cytopathic vs. antiviral immune responses of T cells and natural killer cells. During development of nonalcoholic steatohepatitis, CCL2 and its receptor are up-regulated in the liver, where they promote macrophage accumulation, inflammation, fibrosis, and steatosis, as well as in adipose tissue. CCL2 signaling thereby links hepatic and systemic inflammation related to metabolic disorders and insulin resistance. Several chemokine signaling pathways also promote hepatic fibrosis. Recent studies have shown that other chemokines and immune cells have anti-inflammatory and antifibrotic activities. Chemokines and their receptors can also contribute to the pathogenesis of hepatocellular carcinoma, promoting proliferation of cancer cells, the inflammatory microenvironment of the tumor, evasion of the immune response, and angiogenesis. We review the roles of different chemokines in the pathogenesis of liver diseases and their potential use as biomarkers or therapeutic targets.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhsV2ltbnK&md5=305d6418605e9b6b38bb6c5eb09d0c6c

     
318. 318

     Kanda, H.; Tateya, S.; Tamori, Y.; Kotani, K.; Hiasa, K.; Kitazawa, R.; Kitazawa, S.; Miyachi, H.; Maeda, S.; Egashira, K.; Kasuga, M. MCP-1 Contributes to Macrophage Infiltration into Adipose Tissue, Insulin Resistance, and Hepatic Steatosis in Obesity. J. Clin. Invest. 2006, 116, 1494– 1505,  DOI: 10.1172/JCI26498

     [Crossref], [PubMed], [CAS], Google Scholar

     318

     MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity

     Kanda, Hajime; Tateya, Sanshiro; Tamori, Yoshikazu; Kotani, Ko; Hiasa, Ken-ichi; Kitazawa, Riko; Kitazawa, Sohei; Miyachi, Hitoshi; Maeda, Sakan; Egashira, Kensuke; Kasuga, Masato

     Journal of Clinical Investigation (2006), 116 (6), 1494-1505CODEN: JCINAO; ISSN:0021-9738. (American Society for Clinical Investigation)

     Adipocytes secrete a variety of bioactive mols. that affect the insulin sensitivity of other tissues. We now show that the abundance of monocyte chemoattractant protein-1 (MCP-1) mRNA in adipose tissue and the plasma concn. of MCP-1 were increased both in genetically obese diabetic (db/db) mice and in WT mice with obesity induced by a high-fat diet. Mice engineered to express an MCP-1 transgene in adipose tissue under the control of the aP2 gene promoter exhibited insulin resistance, macrophage infiltration into adipose tissue, and increased hepatic triglyceride content. Furthermore, insulin resistance, hepatic steatosis, and macrophage accumulation in adipose tissue induced by a high-fat diet were reduced extensively in MCP-1 homozygous KO mice compared with WT animals. Finally, acute expression of a dominant-neg. mutant of MCP-1 ameliorated insulin resistance in db/db mice and in WT mice fed a high-fat diet. These findings suggest that an increase in MCP-1 expression in adipose tissue contributes to the macrophage infiltration into this tissue, insulin resistance, and hepatic steatosis assocd. with obesity in mice.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XlsFWrtLo%253D&md5=2b847834b905fcb16c54703b4b6c3ebf

     
319. 319

     Weisberg, S. P.; Hunter, D.; Huber, R.; Lemieux, J.; Slaymaker, S.; Vaddi, K.; Charo, I.; Leibel, R. L.; Ferrante, A. W., Jr. CCR2 Modulates Inflammatory and Metabolic Effects of High-Fat Feeding. J. Clin. Invest. 2006, 116, 115– 124,  DOI: 10.1172/JCI24335

     [Crossref], [PubMed], [CAS], Google Scholar

     319

     CCR2 modulates inflammatory and metabolic effects of high-fat feeding

     Weisberg, Stuart P.; Hunter, Deborah; Huber, Reid; Lemieux, Jacob; Slaymaker, Sarah; Vaddi, Kris; Charo, Israel; Leibel, Rudolph L.; Ferrante, Anthony W., Jr.

     Journal of Clinical Investigation (2006), 116 (1), 115-124CODEN: JCINAO; ISSN:0021-9738. (American Society for Clinical Investigation)

     The C-C motif chemokine receptor-2 (CCR2) regulates monocyte and macrophage recruitment and is necessary for macrophage-dependent inflammatory responses and the development of atherosclerosis. Although adipose tissue expression and circulating concns. of CCL2 (also known as MCP1), a high-affinity ligand for CCR2, are elevated in obesity, the role of CCR2 in metabolic disorders, including insulin resistance, hepatic steatosis, and inflammation assocd. with obesity, has not been studied. To det. what role CCR2 plays in the development of metabolic phenotypes, we studied the effects of Ccr2 genotype on the development of obesity and its assocd. phenotypes. Genetic deficiency in Ccr2 reduced food intake and attenuated the development of obesity in mice fed a high-fat diet. In obese mice matched for adiposity, Ccr2 deficiency reduced macrophage content and the inflammatory profile of adipose tissue, increased adiponectin expression, ameliorated hepatic steatosis, and improved systemic glucose homeostasis and insulin sensitivity. In mice with established obesity, short-term treatment with a pharmacol. antagonist of CCR2 lowered macrophage content of adipose tissue and improved insulin sensitivity without significantly altering body mass or improving hepatic steatosis. These data suggest that CCR2 influences the development of obesity and assocd. adipose tissue inflammation and systemic insulin resistance and plays a role in the maintenance of adipose tissue macrophages and insulin resistance once obesity and its metabolic consequences are established.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XjslOhsw%253D%253D&md5=b607f223e804182a5fb91500a50c8fae

     
320. 320

     Kitade, H.; Sawamoto, K.; Nagashimada, M.; Inoue, H.; Yamamoto, Y.; Sai, Y.; Takamura, T.; Yamamoto, H.; Miyamoto, K.; Ginsberg, H. N.; Mukaida, N.; Kaneko, S.; Ota, T. CCR5 Plays a Critical Role in Obesity-Induced Adipose Tissue Inflammation and Insulin Resistance by Regulating Both Macrophage Recruitment and M1/M2 Status. Diabetes 2012, 61, 1680– 1690,  DOI: 10.2337/db11-1506

     [Crossref], [PubMed], [CAS], Google Scholar

     320

     CCR5 plays a critical role in obesity-induced adipose tissue inflammation and insulin resistance by regulating both macrophage recruitment and M1/M2 status

     Kitade, Hironori; Sawamoto, Kazuki; Nagashimada, Mayumi; Inoue, Hiroshi; Yamamoto, Yasuhiko; Sai, Yoshimichi; Takamura, Toshinari; Yamamoto, Hiroshi; Miyamoto, Ken-ichi; Ginsberg, Henry N.; Mukaida, Naofumi; Kaneko, Shuichi; Ota, Tsuguhito

     Diabetes (2012), 61 (7), 1680-1690CODEN: DIAEAZ; ISSN:0012-1797. (American Diabetes Association, Inc.)

     C-C motif chemokine receptor (CCR)2 and its ligand, monocyte chemoattractant protein (MCP)-1, are pivotal for adipose tissue macrophage (ATM) recruitment and the development of insulin resistance. However, other chemokine systems also may play a role in these processes. In this study, we investigated the role of CCR5 in obesity-induced adipose tissue inflammation and insulin resistance. We analyzed expression levels of CCR5 and its ligands in white adipose tissue (WAT) of genetically (ob/ob) and high-fat (HF) diet-induced obese (DIO) mice. Furthermore, we examd. the metabolic phenotype of Ccr5-/- mice. CCR5 and its ligands were markedly upregulated in WAT of DIO and ob/ob mice. Fluorescence-activated cell sorter anal. also revealed that DIO mice had a robust increase in CCR5+ cells within ATMs compared with chow-fed mice. Furthermore, Ccr5-/- mice were protected from insulin resistance, glucose intolerance, and hepatic steatosis induced by HF feeding. The effects of loss of CCR5 were related to both redn. of total ATM content and an M2-dominant shift in ATM polarization. It is noteworthy that transplantation of Ccr5-/- bone marrow was sufficient to protect against impaired glucose tolerance. CCR5 plays a crit. role in ATM recruitment and polarization and subsequent development of insulin resistance.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtVCrs7zK&md5=f63f905debf98dec9d8433d584e6e4ec

     
321. 321

     Galastri, S.; Zamara, E.; Milani, S.; Novo, E.; Provenzano, A.; Delogu, W.; Vizzutti, F.; Sutti, S.; Locatelli, I.; Navari, N.; Vivoli, E.; Caligiuri, A.; Pinzani, M.; Albano, E.; Parola, M.; Marra, F. Lack of CC Chemokine Ligand 2 Differentially Affects Inflammation and Fibrosis According to the Genetic Background in a Murine Model of Steatohepatitis. Clin. Sci. 2012, 123, 459– 471,  DOI: 10.1042/CS20110515

     [Crossref], [PubMed], [CAS], Google Scholar

     321

     Lack of CC chemokine ligand 2 differentially affects inflammation and fibrosis according to the genetic background in a murine model of steatohepatitis

     Galastri, Sara; Zamara, Elena; Milani, Stefano; Novo, Erica; Provenzano, Angela; Delogu, Wanda; Vizzutti, Francesco; Sutti, Salvatore; Locatelli, Irene; Navari, Nadia; Vivoli, Elisa; Caligiuri, Alessandra; Pinzani, Massimo; Albano, Emanuele; Parola, Maurizio; Marra, Fabio

     Clinical Science (2012), 123 (7), 459-471CODEN: CSCIAE; ISSN:1470-8736. (Portland Press Ltd.)

     Expression of CCL2 (CC chemokine ligand 2) (or monocyte chemoattractant protein-1) regulates inflammatory cell infiltration in the liver and adipose tissue, favoring steatosis. However, its role in the pathogenesis of steatohepatitis is still uncertain. In the present study, we investigated the development of non-alc. steatohepatitis induced by an MCD diet (methionine/choline-deficient diet) in mice lacking the CCL2 gene on two different genetic backgrounds, namely Balb/C and C57/Bl6J. WT (wild-type) and CCL2-KO (knockout) mice were fed on a lipid-enriched MCD diet or a control diet for 8 wk. In Balb/C mice fed on the MCD diet, a lack of CCL2 was assocd. with lower ALT (alanine transaminase) levels and reduced infiltration of inflammatory cells, together with a lower generation of oxidative-stress-related products. Sirius Red staining demonstrated pericellular fibrosis in zone 3, and image anal. showed a significantly lower matrix accumulation in CCL2-KO mice. This was assocd. with reduced hepatic expression of TGF-β (transforming growth factor-β), type I procollagen, TIMP-1 (tissue inhibitor of metalloproteinases-1) and α-smooth muscle actin. In contrast, in mice on a C57Bl/6 background, neither ALT levels nor inflammation or fibrosis were significantly different comparing WT and CCL2-KO animals fed on an MCD diet. In agreement, genes related to fibrogenesis were expressed to comparable levels in the two groups of animals. Comparison of the expression of several genes involved in inflammation and repair demonstrated that IL (interleukin)-4 and the M2 marker MGL-1 (macrophage galactose-type C-type lectin 1) were differentially expressed in Balb/C and C57Bl/6 mice. No significant differences in the degree of steatosis were obsd. in all groups of mice fed on the MCD diet. We conclude that, in exptl. murine steatohepatitis, the effects of CCL2 deficiency are markedly dependent on the genetic background.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xhs1WqsLrJ&md5=31854cd3c26ab56f418eee790f7b62ee

     
322. 322

     Mitchell, C.; Couton, D.; Couty, J. P.; Anson, M.; Crain, A. M.; Bizet, V.; Renia, L.; Pol, S.; Mallet, V.; Gilgenkrantz, H. Dual Role of CCR2 in the Constitution and the Resolution of Liver Fibrosis in Mice. Am. J. Pathol. 2009, 174, 1766– 1775,  DOI: 10.2353/ajpath.2009.080632

     [Crossref], [PubMed], [CAS], Google Scholar

     322

     Dual role of CCR2 in the constitution and the resolution of liver fibrosis in mice

     Mitchell, Claudia; Couton, Dominique; Couty, Jean-Pierre; Anson, Marie; Crain, Anne-Marie; Bizet, Vinciane; Renia, Laurent; Pol, Stanislas; Mallet, Vincent; Gilgenkrantz, Helene

     American Journal of Pathology (2009), 174 (5), 1766-1775CODEN: AJPAA4; ISSN:0002-9440. (American Society for Investigative Pathology)

     Inflammation has been shown to induce the progression of fibrosis in response to liver injury. Among inflammatory cells, macrophages and lymphocytes play major roles in both the constitution and resoln. of liver fibrosis. The chemokine receptor CCR2 is involved in the recruitment of monocytes to injury sites, and it is known to be induced during the progression of fibrosis in humans. However, its specific role during this process has not yet been unveiled. We first demonstrated that, compared with wild-type mice, CCR2 knockout animals presented a delay in liver injury after acute CCl4 injection, accompanied by a redn. in infiltrating macrophage populations. We then induced fibrosis using repeated injections of CCl4 and obsd. a significantly lower level of fibrotic scars at the peak of fibrosis in mutant animals compared with control mice. This diminished fibrosis was assocd. with a redn. in F4/80+CD11b+ and CD11c+ populations at the sites of injury. Subsequent anal. of the kinetics of the resoln. of fibrosis showed that fibrosis rapidly regressed in wild-type, but not in CCR2-/- mice. The persistence of hepatic injury in mutant animals was correlated with sustained tissue inhibitor of metalloproteinase-1 mRNA expression levels and a redn. in matrix metalloproteinase-2 and matrix metalloproteinase-13 expression levels. In conclusion, these findings underline the role of the CCR2 signaling pathway in both the constitution and resoln. of liver fibrotic scars.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXlvVWmsr4%253D&md5=777dbfedcd9370d98f2fdecd5b51e3f5

     
323. 323

     Seki, E.; De Minicis, S.; Gwak, G. Y.; Kluwe, J.; Inokuchi, S.; Bursill, C. A.; Llovet, J. M.; Brenner, D. A.; Schwabe, R. F. CCR1 and CCR5 Promote Hepatic Fibrosis in Mice. J. Clin. Invest. 2009, 119, 1858– 1870,  DOI: 10.1172/JCI37444

     [Crossref], [PubMed], [CAS], Google Scholar

     323

     CCR1 and CCR5 promote hepatic fibrosis in mice

     Seki, Ekihiro; De Minicis, Samuele; Gwak, Geum-Youn; Kluwe, Johannes; Inokuchi, Sayaka; Bursill, Christina A.; Llovet, Josep M.; Brenner, David A.; Schwabe, Robert F.

     Journal of Clinical Investigation (2009), 119 (7), 1858-1870CODEN: JCINAO; ISSN:0021-9738. (American Society for Clinical Investigation)

     Hepatic fibrosis develops as a response to chronic liver injury and almost exclusively occurs in a proinflammatory environment. However, the role of inflammatory mediators in fibrogenic responses of the liver is only poorly understood. The authors therefore investigated the role of CC chemokines and their receptors in hepatic fibrogenesis. The CC chemokines MIP-1α, MIP-1β, and RANTES and their receptors CCR1 and CCR5 were strongly upregulated in 2 exptl. mouse models of fibrogenesis. Neutralization of CC chemokines by the broad-spectrum CC chemokine inhibitor 35k efficiently reduced hepatic fibrosis, and CCR1- and CCR5-deficient mice displayed substantially reduced hepatic fibrosis and macrophage infiltration. Anal. of fibrogenesis in CCR1- and CCR5-chimeric mice revealed that CCR1 mediates its profibrogenic effects in BM-derived cells, whereas CCR5 mediates its profibrogenic effects in resident liver cells. CCR5 promoted hepatic stellate cell (HSC) migration through a redox-sensitive, PI3K-dependent pathway. Both CCR5-deficient HSCs and CCR1- and CCR5-deficient Kupffer cells displayed strong suppression of CC chemokine-induced migration. Finally, the authors detected marked upregulation of RANTES, CCR1, and CCR5 in patients with hepatic cirrhosis, confirming activation of the CC chemokine system in human fibrogenesis. The authors' data therefore support a role for the CC chemokine system in hepatic fibrogenesis and suggest distinct roles for CCR1 and CCR5 in Kupffer cells and HSCs.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXosVCku7k%253D&md5=b9545141dc4c6dfd249f97f534e2e27f

     
324. 324

     Shiraishi, M.; Aramaki, Y.; Seto, M.; Imoto, H.; Nishikawa, Y.; Kanzaki, N.; Okamoto, M.; Sawada, H.; Nishimura, O.; Baba, M.; Fujino, M. Discovery of Novel, Potent, and Selective Small-Molecule CCR5 Antagonists as Anti-HIV-1 Agents: Synthesis and Biological Evaluation of Anilide Derivatives with a Quaternary Ammonium Moiety. J. Med. Chem. 2000, 43, 2049– 2063,  DOI: 10.1021/jm9906264

     [ACS Full Text ], [CAS], Google Scholar

     324

     Discovery of Novel, Potent, and Selective Small-Molecule CCR5 Antagonists as Anti-HIV-1 Agents: Synthesis and Biological Evaluation of Anilide Derivatives with a Quaternary Ammonium Moiety

     Shiraishi, Mitsuru; Aramaki, Yoshio; Seto, Masaki; Imoto, Hiroshi; Nishikawa, Youichi; Kanzaki, Naoyuki; Okamoto, Mika; Sawada, Hidekazu; Nishimura, Osamu; Baba, Masanori; Fujino, Masahiko

     Journal of Medicinal Chemistry (2000), 43 (10), 2049-2063CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

     The search for new small-mol. CCR5 antagonists by high-throughput screening (HTS) of the Takeda chem. library using [125I]RANTES and CHO/CCR5 cells led to the discovery of lead compds. with a quaternary ammonium or phosphonium moiety, which were synthesized to investigate new MCP-1 receptor antagonists. A series of novel anilide derivs. with a quaternary ammonium moiety were designed, synthesized, and tested for their CCR5 antagonistic activity. Through the optimization of lead compds., we have found N,N-dimethyl-N-[4-[[[2-(4-methylphenyl)-6,7-dihydro-5H-benzocyclohepten-8-yl]carbonyl]amino]benzyl]tetrahydro-2H-pyran-4-aminium chloride as a highly potent and selective nonpeptide CCR5 antagonist with a IC50 value of 1.4 nM in the binding assay. The synthesis and structure-activity relationships of the title compds. and their related compds. are detailed.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXisFGhsrc%253D&md5=fa4bc03a80d858423cfe7c4f73a53523

     
325. 325

     Seto, M.; Miyamoto, N.; Aikawa, K.; Aramaki, Y.; Kanzaki, N.; Iizawa, Y.; Baba, M.; Shiraishi, M. Orally Active CCR5 Antagonists as Anti-HIV-1 Agents. Part 3: Synthesis and Biological Activities of 1-Benzazepine Derivatives Containing a Sulfoxide Moiety. Bioorg. Med. Chem. 2005, 13, 363– 386,  DOI: 10.1016/j.bmc.2004.10.021

     [Crossref], [PubMed], [CAS], Google Scholar

     325

     Orally active CCR5 antagonists as anti-HIV-1 agents. Part 3: Synthesis and biological activities of 1-benzazepine derivatives containing a sulfoxide moiety

     Seto Masaki; Miyamoto Naoki; Aikawa Katsuji; Aramaki Yoshio; Kanzaki Naoyuki; Iizawa Yuji; Baba Masanori; Shiraishi Mitsuru

     Bioorganic & medicinal chemistry (2005), 13 (2), 363-86 ISSN:0968-0896.

     In order to develop orally active CCR5 antagonists, 1-propyl- or 1-isobutyl-1-benzazepine derivatives containing a sulfoxide moiety have been designed, synthesized, and evaluated for their biological activities. Sulfoxide compounds containing a 2-pyridyl group were first investigated, which led to discovering that the presence of a methylene group between the sulfoxide moiety and 2-pyridyl group was necessary for increased inhibitory activity in a binding assay. After further chemical modification, it was found that replacement of the pyridyl group with an imidazolyl or 1,2,4-triazolyl group enhanced activity in the binding assay and that S-sulfoxide compounds were more active than R-isomers. Particularly, compounds (S)-4r, (S)-4s, and (S)-4w exhibited highly potent CCR5 antagonistic activities (IC50=1.9, 1.7, 1.6 nM, respectively) and inhibitory effects (IC50=1.0, 2.8, 7.7 nM, respectively) in the HIV-1 envelope mediated membrane fusion assay, together with good pharmacokinetic properties in rats. In addition, we established the synthesis of (S)-4r and (S)-4w by asymmetric oxidation with titanium-(S)-(-)-1,1'-bi-2-naphthol complex.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2cnitlarug%253D%253D&md5=a067855ee928284dea47e48a0436b10d

     
326. 326

     Seto, M.; Aramaki, Y.; Imoto, H.; Aikawa, K.; Oda, T.; Kanzaki, N.; Iizawa, Y.; Baba, M.; Shiraishi, M. Orally Active CCR5 Antagonists as Anti-HIV-1 Agents 2: Synthesis and Biological Activities of Anilide Derivatives Containing a Pyridine N-Oxide Moiety. Chem. Pharm. Bull. 2004, 52, 818– 829,  DOI: 10.1248/cpb.52.818

     [Crossref], [PubMed], [CAS], Google Scholar

     326

     Orally active CCR5 antagonists as anti-HIV-1 agents 2: Synthesis and biological activities of anilide derivatives containing a pyridine N-oxide moiety

     Seto, Masaki; Aramaki, Yoshio; Imoto, Hiroshi; Aikawa, Katsuji; Oda, Tsuneo; Kanzaki, Naoyuki; Iizawa, Yuji; Baba, Masanori; Shiraishi, Mitsuru

     Chemical & Pharmaceutical Bulletin (2004), 52 (7), 818-829CODEN: CPBTAL; ISSN:0009-2363. (Pharmaceutical Society of Japan)

     In order to develop orally active CCR5 antagonists, we investigated 1-benzoxepine derivs. contg. new polar substituents, such as phosphonate, phosphine oxide or pyridine N-oxide moieties, as replacements for the previously reported quaternary ammonium moiety. Among these compds., the 2-(α-hydroxybenzyl)pyridine N-oxide exhibited moderate CCR5 antagonistic activity and had an acceptable pharmacokinetic profile in rats. Subsequent chem. modification was performed and compd. I (X = SO2; R = H) possessing the (S)-configuration hydroxy group was found to be more active than the (R)-isomer. Replacement of the 1-benzoxepine ring with a 4-methylphenyl group by a 1-benzazepine ring with a 4-[2-(butoxy)ethoxy]phenyl group enhanced the activity in the binding assay. In addn., introduction of a 3-trifluoromethyl group on the Ph group of the anilide moiety led to greatly increased activity in the HIV-1 envelope-mediated membrane fusion assay. In particular, compd. (S)-I (X = NCH2CHMe2; R = CF3) showed the most potent CCR5 antagonistic activity (IC50=7.2 nM) and inhibitory effect (IC50=5.4 nM) in the fusion assay, together with good pharmacokinetic properties in rats.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXlvFKrtrk%253D&md5=674e3e8557e0732e28a9c20d8944caa3

     
327. 327

     Seto, M.; Aramaki, Y.; Okawa, T.; Miyamoto, N.; Aikawa, K.; Kanzaki, N.; Niwa, S.; Iizawa, Y.; Baba, M.; Shiraishi, M. Orally Active CCR5 Antagonists as Anti-HIV-1 Agents: Synthesis and Biological Activity of 1-Benzothiepine 1,1-Dioxide and 1-Benzazepine Derivatives Containing a Tertiary Amine Moiety. Chem. Pharm. Bull. 2004, 52, 577– 590,  DOI: 10.1248/cpb.52.577

     [Crossref], [PubMed], [CAS], Google Scholar

     327

     Orally active CCR5 antagonists as anti-HIV-1 agents: Synthesis and biological activity of 1-benzothiepine 1,1-dioxide and 1-benzazepine derivatives containing a tertiary amine moiety

     Seto, Masaki; Aramaki, Yoshio; Okawa, Tomohiro; Miyamoto, Naoki; Aikawa, Katsuji; Kanzaki, Naoyuki; Niwa, Shin-ichi; Iizawa, Yuji; Baba, Masanori; Shiraishi, Mitsuru

     Chemical & Pharmaceutical Bulletin (2004), 52 (5), 577-590CODEN: CPBTAL; ISSN:0009-2363. (Pharmaceutical Society of Japan)

     The search for orally active CCR5 antagonists was performed by chem. modification of the 1-benzothiepine 1,1-dioxide 3 and 1-benzazepine 4 lead compds. contg. a tertiary amine moiety. Replacement of Me group with a 2-(C2-4 alkoxy)ethoxy group at the 4-position on the 7-Ph group of the 1-benzothiepine ring resulted in both enhanced activity and significant improvement in the pharmacokinetic properties upon oral administration in rats. Introduction of C2-4 alkyl, Ph or (hetero)arylmethyl groups as the 1-substituent on the 1-benzazepine ring together with the 2-(butoxy)ethoxy group led to further increase of activity. Among the 1-benzazepine derivs., the iso-Bu, benzyl or 1-methylpyrazol-4-ylmethyl compds. were found to exhibit highly potent inhibitory effects, equiv. to the known injectable CCR5 antagonist, in the HIV-1 envelope-mediated membrane fusion assay. In particular, the 1-methylpyrazol-4-ylmethyl compd. showed the most potent CCR5 antagonistic activity (IC50=2.7 nM) and inhibitory effect (IC50=1.2 nM) on membrane fusion, together with good pharmacokinetic properties in rats. The synthesis of 1-benzothiepine 1,1-dioxide and 1-benzazepine derivs. and their biol. activity are described.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXksVyltLk%253D&md5=35221b40ad9cdae0d15d15d91e818732

     
328. 328

     Seto, M.; Aikawa, K.; Miyamoto, N.; Aramaki, Y.; Kanzaki, N.; Takashima, K.; Kuze, Y.; Iizawa, Y.; Baba, M.; Shiraishi, M. Highly Potent and Orally Active CCR5 Antagonists as Anti-HIV-1 Agents: Synthesis and Biological Activities of 1-Benzazocine Derivatives Containing a Sulfoxide Moiety. J. Med. Chem. 2006, 49, 2037– 2048,  DOI: 10.1021/jm0509703

     [ACS Full Text ], [CAS], Google Scholar

     328

     Highly Potent and Orally Active CCR5 Antagonists as Anti-HIV-1 Agents: Synthesis and Biological Activities of 1-Benzazocine Derivatives Containing a Sulfoxide Moiety

     Seto, Masaki; Aikawa, Katsuji; Miyamoto, Naoki; Aramaki, Yoshio; Kanzaki, Naoyuki; Takashima, Katsunori; Kuze, Yoji; Iizawa, Yuji; Baba, Masanori; Shiraishi, Mitsuru

     Journal of Medicinal Chemistry (2006), 49 (6), 2037-2048CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

     Chem. modification was performed on the orally bioavailable and potent CCR5 antagonist sulfoxide compd. I, mainly focusing on replacement of the [6,7]-fused 1-benzazepine nucleus. Ring-expanded [6,8]-, [6,9]-, and [6,10]-fused compds. contg. S-sulfoxide moieties were prepd. and evaluated for biol. activities which led to 1-benzazocine and 1-benzazonine compds. that exhibited potent inhibitory activities. 1-Benzazocine compds. possessing the S-sulfoxide moiety showed greater potency than I in a fusion assay. Further investigation in a multi-round infection assay showed that the 1-isobutyl-1-benzazocine compd. II, contg. the S-[[(1-propyl-1H-imidazol)-5-yl]methyl]sulfinyl group, showed the most potent anti-HIV-1 activity. II (TAK-652) also inhibited the replication of six macrophage-tropic HIV-1 clin. isolates in peripheral blood mononuclear cells. It was also absorbed after oral administration in rats, dogs, and monkeys and was thus selected as a clin. candidate. The synthesis and biol. activity of II and derivs. are described.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XhvVCjsrY%253D&md5=e579dea40031ca3ac3d7b2d96875ab4c

     
329. 329

     Tacke, F. Cenicriviroc for the Treatment of Non-Alcoholic Steatohepatitis and Liver Fibrosis. Expert Opin. Invest. Drugs 2018, 27, 301– 311,  DOI: 10.1080/13543784.2018.1442436

     [Crossref], [PubMed], [CAS], Google Scholar

     329

     Cenicriviroc for the treatment of non-alcoholic steatohepatitis and liver fibrosis

     Tacke, Frank

     Expert Opinion on Investigational Drugs (2018), 27 (3), 301-311CODEN: EOIDER; ISSN:1354-3784. (Taylor & Francis Ltd.)

     : Nonalcoholic fatty liver disease (NAFLD) has an increasing prevalence worldwide. At present, no specific pharmacotherapy is approved for NAFLD. Simple steatosis and nonalcoholic steatohepatitis (NASH) can progress to liver fibrosis that is assocd. with mortality in NAFLD. The recruitment of inflammatory monocytes and macrophages via chemokine receptor CCR2 as well as of lymphocytes and hepatic stellate cells via CCR5 promote the progression of NASH to fibrosis. I summarize preclin. and clin. data on the efficacy and safety of the dual CCR2/CCR5 inhibitor cenicriviroc (CVC, also TBR-652 or TAK-652) for the treatment of NASH and fibrosis. In animal models of liver diseases, CVC potently inhibits macrophage accumulation in the liver and ameliorates fibrosis. In a phase 2b clin. trial (CENTAUR) on 289 patients with NASH and fibrosis, CVC consistently demonstrated liver fibrosis improvement after 1 yr of therapy and had an excellent safety profile, leading to the implementation of a phase 3 trial (AURORA). Preclin. and clin. data support the development of CVC as a safe and potent antifibrotic agent. However, open questions around CVC are the durability of antifibrotic responses, divergent effects on NASH vs. fibrosis, potential long-term concerns and the expected path to approval.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXjt12kurg%253D&md5=2666dffff593043448dbd9a4230e1c49

     
330. 330

     Lefebvre, E.; Moyle, G.; Reshef, R.; Richman, L. P.; Thompson, M.; Hong, F.; Chou, H. L.; Hashiguchi, T.; Plato, C.; Poulin, D.; Richards, T.; Yoneyama, H.; Jenkins, H.; Wolfgang, G.; Friedman, S. L. Antifibrotic Effects of the Dual CCR2/CCR5 Antagonist Cenicriviroc in Animal Models of Liver and Kidney Fibrosis. PLoS One 2016, 11, e0158156  DOI: 10.1371/journal.pone.0158156

     [Crossref], [PubMed], [CAS], Google Scholar

     330

     Antifibrotic effects of the dual CCR2/CCR5 antagonist cenicriviroc in animal models of liver and kidney fibrosis

     Lefebvre, Eric; Moyle, Graeme; Reshef, Ran; Richman, Lee P.; Thompson, Melanie; Hong, Feng; Chou, Hsin-l; Hashiguchi, Taishi; Plato, Craig; Poulin, Dominic; Richards, Toni; Yoneyama, Hiroyuki; Jenkins, Helen; Wolfgang, Grushenka; Friedman, Scott L.

     PLoS One (2016), 11 (6), e0158156/1-e0158156/19CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)

     Background & Aims: Interactions between C-C chemokine receptor types 2 (CCR2) and 5 (CCR5) and their ligands, including CCL2 and CCL5, mediate fibrogenesis by promoting monocyte/macrophage recruitment and tissue infiltration, as well as hepatic stellate cell activation. Cenicriviroc (CVC) is an oral, dual CCR2/CCR5 antagonist with nanomolar potency against both receptors. CVC's anti-inflammatory and antifibrotic effects were evaluated in a range of preclin. models of inflammation and fibrosis. Methods: Monocyte/macrophage recruitment was assessed in vivo in a mouse model of thioglycollate-induced peritonitis. CCL2-induced chemotaxis was evaluated ex vivo on mouse monocytes. CVC's antifibrotic effects were evaluated in a thioacetamide-induced rat model of liver fibrosis and mouse models of diet-induced non-alc. steatohepatitis (NASH) and renal fibrosis. Study assessments included body and liver/kidney wt., liver function test, liver/kidney morphol. and collagen deposition, fibrogenic gene and protein expression, and pharmacokinetic analyses. Results: CVC significantly reduced monocyte/macrophage recruitment in vivo at doses ≥20 mg/kg/day (p < 0.05). At these doses, CVC showed antifibrotic effects, with significant redns. in collagen deposition (p < 0.05), and collagen type 1 protein and mRNA expression across the three animal models of fibrosis. In the NASH model, CVC significantly reduced the non-alc. fatty liver disease activity score (p < 0.05 vs. controls). CVC treatment had no notable effect on body or liver/kidney wt. Conclusions: CVC displayed potent anti-inflammatory and antifibrotic activity in a range of animal fibrosis models, supporting human testing for fibrotic diseases. Further exptl. studies are needed to clarify the underlying mechanisms of CVC's antifibrotic effects. A Phase 2b study in adults with NASH and liver fibrosis is fully enrolled (CENTAUR Study 652-2-203; NCT02217475).

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhslWgt73N&md5=b0a31196b1100633505aa59df117d73c

     
331. 331

     Friedman, S.; Sanyal, A.; Goodman, Z.; Lefebvre, E.; Gottwald, M.; Fischer, L.; Ratziu, V. Efficacy and Safety Study of Cenicriviroc for the Treatment of Non-Alcoholic Steatohepatitis in Adult Subjects with Liver Fibrosis: CENTAUR Phase 2b Study Design. Contemp. Clin. Trials 2016, 47, 356– 365,  DOI: 10.1016/j.cct.2016.02.012

     [Crossref], [PubMed], [CAS], Google Scholar

     331

     Efficacy and safety study of cenicriviroc for the treatment of non-alcoholic steatohepatitis in adult subjects with liver fibrosis: CENTAUR Phase 2b study design

     Friedman Scott; Sanyal Arun; Goodman Zachary; Lefebvre Eric; Gottwald Mildred; Fischer Laurent; Ratziu Vlad

     Contemporary clinical trials (2016), 47 (), 356-65 ISSN:.

     BACKGROUND: Non-alcoholic steatohepatitis (NASH) is often accompanied by liver fibrosis, which can progress to cirrhosis; C-C chemokine receptors type 2 and 5 (CCR2/CCR5), which mediate interactions driving inflammation and fibrosis, are promising treatment targets. Cenicriviroc (CVC), a dual-CCR2/CCR5 antagonist, has potent anti-inflammatory and antifibrotic activity in animal models; in HIV-positive subjects it reduced soluble CD14 levels, aspartate aminotransferase-to-platelet count ratio index, and non-invasive hepatic fibrosis risk scores; favorable tolerability was demonstrated in ~600 subjects. Efficacy and safety of CVC 150 mg for treating NASH with liver fibrosis are being evaluated over 2 years (primary endpoint at Year 1 [Y1]). DESIGN: Phase 2b, randomized, double-blind, placebo-controlled, multinational study (CENTAUR; NCT02217475). Adults with histological evidence of NASH, non-alcoholic fatty liver disease activity score (NAS) ≥ 4, and liver fibrosis (stages 1-3 NASH clinical research network system) enrolled. Subjects have increased risk of progression to cirrhosis due to ≥1 characteristic: type 2 diabetes; body mass index > 25 kg/m(2) with ≥1 feature of metabolic syndrome; bridging fibrosis and/or NAS ≥ 5. Liver biopsy evaluation at Screening, Y1, and Year 2 (Y2). OBJECTIVES: Assess histologic improvement (≥2-point in NAS with ≥1-point improvement in >1 category) without worsening of fibrosis at Y1 (primary); evaluate complete NASH resolution without worsening of fibrosis at Y2 (key secondary). DISCUSSION: CENTAUR is the first prospective study evaluating an oral agent exclusively enrolling subjects with NASH and liver fibrosis, with increased risk of developing cirrhosis. It will compare shorter versus longer CVC treatment and assess correlations between decreased inflammation and fibrosis.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC28jntFOrtg%253D%253D&md5=7370c1cbc24b36e1ab5e5e7f4ff2ea3a

     
332. 332

     Friedman, S. L.; Ratziu, V.; Harrison, S. A.; Abdelmalek, M. F.; Aithal, G. P.; Caballeria, J.; Francque, S.; Farrell, G.; Kowdley, K. V.; Craxi, A.; Simon, K.; Fischer, L.; Melchor-Khan, L.; Vest, J.; Wiens, B. L.; Vig, P.; Seyedkazemi, S.; Goodman, Z.; Wong, V. W.; Loomba, R.; Tacke, F.; Sanyal, A.; Lefebvre, E. A Randomized, Placebo-Controlled Trial of Cenicriviroc for Treatment of Nonalcoholic Steatohepatitis with Fibrosis. Hepatology 2018, 67, 1754– 1767,  DOI: 10.1002/hep.29477

     [Crossref], [PubMed], [CAS], Google Scholar

     332

     A randomized, placebo-controlled trial of cenicriviroc for treatment of nonalcoholic steatohepatitis with fibrosis

     Friedman, Scott L.; Ratziu, Vlad; Harrison, Stephen A.; Abdelmalek, Manal F.; Aithal, Guruprasad P.; Caballeria, Juan; Francque, Sven; Farrell, Geoffrey; Kowdley, Kris V.; Craxi, Antonio; Simon, Krzysztof; Fischer, Laurent; Melchor-Khan, Liza; Vest, Jeffrey; Wiens, Brian L.; Vig, Pamela; Seyedkazemi, Star; Goodman, Zachary; Wong, Vincent Wai-Sun; Loomba, Rohit; Tacke, Frank; Sanyal, Arun; Lefebvre, Eric

     Hepatology (Hoboken, NJ, United States) (2018), 67 (5), 1754-1767CODEN: HPTLD9; ISSN:0270-9139. (John Wiley & Sons, Inc.)

     The aim of this study was to evaluate cenicriviroc (CVC), a dual antagonist of C-C chemokine receptor types 2 and 5, for treatment of nonalcoholic steatohepatitis (NASH) with liver fibrosis (LF). A randomized, double-blind, multinational phase 2b study enrolled subjects with NASH, a nonalcoholic fatty liver disease activity score (NAS) ≥4, and LF (stages 1-3, NASH Clin. Research Network) at 81 clin. sites. Subjects (N = 289) were randomly assigned CVC 150 mg or placebo. Primary outcome was ≥2-point improvement in NAS and no worsening of fibrosis at year 1. Key secondary outcomes were: resoln. of steatohepatitis (SH) and no worsening of fibrosis; improvement in fibrosis by ≥1 stage and no worsening of SH. Biomarkers of inflammation and adverse events were assessed. Full study recruitment was achieved. The primary endpoint of NAS improvement in the intent-to-treat population and resoln. of SH was achieved in a similar proportion of subjects on CVC (N = 145) and placebo (N = 144; 16% vs. 19%, P = 0.52 and 8% vs. 6%, P = 0.49, resp.). However, the fibrosis endpoint was met in significantly more subjects on CVC than placebo (20% vs. 10%; P = 0.02). Treatment benefits were greater in those with higher disease activity and fibrosis stage at baseline. Biomarkers of systemic inflammation were reduced with CVC. Safety and tolerability of CVC were comparable to placebo. Conclusion: After 1 yr of CVC treatment, twice as many subjects achieved improvement in fibrosis and no worsening of SH compared with placebo. Given the urgent need to develop antifibrotic therapies in NASH, these findings warrant phase 3 evaluation. (Hepatol. 2018;67:1754-1767).

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXotlCms7g%253D&md5=a712985806b627b992895637d9f59b58

     
333. 333

     Gomez-Sanchez, E.; Gomez-Sanchez, C. E. The Multifaceted Mineralocorticoid Receptor. Compr. Physiol. 2014, 4, 965– 994,  DOI: 10.1002/cphy.c130044

     [Crossref], [PubMed], [CAS], Google Scholar

     333

     The multifaceted mineralocorticoid receptor

     Gomez-Sanchez Elise; Gomez-Sanchez Celso E

     Comprehensive Physiology (2014), 4 (3), 965-94 ISSN:.

     The primary adrenal cortical steroid hormones, aldosterone, and the glucocorticoids cortisol and corticosterone, act through the structurally similar mineralocorticoid (MR) and glucocorticoid receptors (GRs). Aldosterone is crucial for fluid, electrolyte, and hemodynamic homeostasis and tissue repair; the significantly more abundant glucocorticoids are indispensable for energy homeostasis, appropriate responses to stress, and limiting inflammation. Steroid receptors initiate gene transcription for proteins that effect their actions as well as rapid non-genomic effects through classical cell signaling pathways. GR and MR are expressed in many tissues types, often in the same cells, where they interact at molecular and functional levels, at times in synergy, others in opposition. Thus the appropriate balance of MR and GR activation is crucial for homeostasis. MR has the same binding affinity for aldosterone, cortisol, and corticosterone. Glucocorticoids activate MR in most tissues at basal levels and GR at stress levels. Inactivation of cortisol and corticosterone by 11β-HSD2 allows aldosterone to activate MR within aldosterone target cells and limits activation of the GR. Under most conditions, 11β-HSD1 acts as a reductase and activates cortisol/corticosterone, amplifying circulating levels. 11β-HSD1 and MR antagonists mitigate inappropriate activation of MR under conditions of oxidative stress that contributes to the pathophysiology of the cardiometabolic syndrome; however, MR antagonists decrease normal MR/GR functional interactions, a particular concern for neurons mediating cognition, memory, and affect.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2cfjvFyhtQ%253D%253D&md5=c077ad6930c7bc98d0ae6291edd11de9

     
334. 334

     Nishiyama, A.; Yao, L.; Nagai, Y.; Miyata, K.; Yoshizumi, M.; Kagami, S.; Kondo, S.; Kiyomoto, H.; Shokoji, T.; Kimura, S.; Kohno, M.; Abe, Y. Possible Contributions of Reactive Oxygen Species and Mitogen-Activated Protein Kinase to Renal Injury in Aldosterone/Salt-Induced Hypertensive Rats. Hypertension 2004, 43, 841– 848,  DOI: 10.1161/01.HYP.0000118519.66430.22

     [Crossref], [PubMed], [CAS], Google Scholar

     334

     Possible Contributions of Reactive Oxygen Species and Mitogen-Activated Protein Kinase to Renal Injury in Aldosterone/Salt-Induced Hypertensive Rats

     Nishiyama, Akira; Yao, Li; Nagai, Yukiko; Miyata, Kayoko; Yoshizumi, Masanori; Kagami, Shoji; Kondo, Shuji; Kiyomoto, Hideyasu; Shokoji, Takatomi; Kimura, Shoji; Kohno, Masakazu; Abe, Youichi

     Hypertension (2004), 43 (4), 841-848CODEN: HPRTDN; ISSN:0194-911X. (Lippincott Williams & Wilkins)

     Studies were performed to test the hypothesis that reactive oxygen species (ROS) and mitogen-activated protein kinase (MAPK) contribute to the pathogenesis of aldosterone/salt-induced renal injury. Rats were given 1% NaCl to drink and were treated with one of the following combinations for 6 wk: vehicle (0.5% ethanol, SC, n=6); aldosterone (0.75 μg/H, SC, n=8); aldosterone plus a selective mineralocorticoid receptor antagonist; eplerenone (0.125% in chow, n=8); aldosterone plus an antioxidant; and tempol (3 mmol/L in drinking soln., n=8). The activities of MAPKs, including extracellular signal-regulated kinases (ERK)1/2, c-Jun-NH2-terminal kinases (JNK), p38MAPK, and big-MAPK-1 (BMK1) in renal cortical tissues were measured by Western blot anal. Aldosterone-infused rats showed higher systolic blood pressure (165±5 mm Hg) and urinary excretion of protein (106±24 mg/d) than vehicle-infused rats (118±3 mm Hg and 10±3 mg/d). Renal cortical mRNA expression of p22phox, Nox-4, and gp91phox, measured by real-time polymerase chain reaction, was increased in aldosterone-infused rats by 2.3, 4.3, and 3.0-fold, resp. Thiobarbituric acid-reactive substances (TBARS) content in renal cortex was also higher in aldosterone (0.23±0.02) than vehicle-infused rats (0.09±0.01 nmol/mg protein). ERK1/2, JNK, and BMK1 activities were significantly elevated in aldosterone-infused rats by 3.3, 2.3, and 3.0-fold, resp., whereas p38MAPK activity was not changed. Concurrent administration of eplerenone or tempol to aldosterone-infused rats prevented the development of hypertension (127±2 and 125±5 mm Hg), and the elevations of urinary excretion of protein (10±2 and 9±2 mg/day) or TBARS contents (0.08±0.01 and 0.11±0.01 nmol/mg protein). Furthermore, eplerenone and tempol treatments normalized the activities of ERK1/2, JNK, and BMK1. These data suggest that ROS and MAPK play a role in the progression of renal injury induced by chronic elevations in aldosterone.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXit12mtr0%253D&md5=fee70e1d46339a7f7aa3ec5abec1b942

     
335. 335

     Jaffe, I. Z.; Mendelsohn, M. E. Angiotensin II and Aldosterone Regulate Gene Transcription via Functional Mineralocortocoid Receptors in Human Coronary Artery Smooth Muscle Cells. Circ. Res. 2005, 96, 643– 650,  DOI: 10.1161/01.RES.0000159937.05502.d1

     [Crossref], [PubMed], [CAS], Google Scholar

     335

     Angiotensin II and Aldosterone Regulate Gene Transcription Via Functional Mineralocorticoid Receptors in Human Coronary Artery Smooth Muscle Cells

     Jaffe, Iris Z.; Mendelsohn, Michael E.

     Circulation Research (2005), 96 (6), 643-650CODEN: CIRUAL; ISSN:0009-7330. (Lippincott Williams & Wilkins)

     Inhibition or blockade of the angiotensin-aldosterone system consistently decreases ischemic cardiovascular events in clin. trials. The steroid hormone aldosterone acts by binding to the mineralocorticoid receptor (MR), a ligand activated transcription factor that is a member of the nuclear hormone receptor superfamily. MR binds and is activated by aldosterone and cortisol with equal affinity, but MR activation by cortisol is diminished in tissues that express the cortisol-inactivating enzyme 11-β-hydroxysteroid-dehydrogenase-2 (11βHSD2). Although previous studies support that the vasculature is a target tissue of aldosterone, MR-mediated gene expression in vascular cells has not been demonstrated or systematically explored. The authors investigated whether functional MR and 11βHSD2 are expressed in human blood vessels. Human coronary and aortic vascular smooth muscle cells (VSMCs) express mRNA and protein for both MR and 11βHSD2. The endogenous VSMC MR mediates aldosterone-dependent gene expression, which is blocked by the competitive MR antagonist spironolactone. Inhibition of 11βHSD2 in coronary artery VSMCs enhances gene transactivation by cortisol, supporting that the VSMC 11βHSD2 is functional. Angiotensin II also activates MR-mediated gene transcription in coronary artery VSMCs. Angiotensin II activation of MR-mediated gene expression is inhibited by both the AT1 receptor blocker losartan and by spironolactone, but not by aldosterone synthase inhibition. Microarray and quant. RT-PCR expts. show that aldosterone activates expression of endogenous human coronary VSMC genes, including several involved in vascular fibrosis, inflammation, and calcification. These data support a new MR-dependent mechanism by which aldosterone and angiotensin II influence ischemic cardiovascular events, and suggest that ACE inhibitors and MR antagonists may decrease clin. ischemic events by inhibiting MR-dependent gene expression in vascular cells.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXis1elsL0%253D&md5=63ff46d8687cc503ce6c3854305a4044

     
336. 336

     Gilbert, K. C.; Brown, N. J. Aldosterone and Inflammation. Curr. Opin. Endocrinol., Diabetes Obes. 2010, 17, 199– 204,  DOI: 10.1097/MED.0b013e3283391989

     [Crossref], [PubMed], [CAS], Google Scholar

     336

     Aldosterone and inflammation

     Gilbert, Kimberly C.; Brown, Nancy J.

     Current Opinion in Endocrinology, Diabetes and Obesity (2010), 17 (3), 199-204CODEN: COEDFK; ISSN:1752-296X. (Lippincott Williams & Wilkins)

     Purpose of review: Aldosterone causes tissue inflammation leading to fibrosis and remodeling in the heart, vasculature, and kidney. We summarize recent data regarding the mechanism(s) through which aldosterone stimulates inflammation. Recent findings: Studies elucidate the cell-specific effects of mineralocorticoid receptor activation on inflammatory cell infiltration and adhesion, and highlight the role of the macrophage in the development of vascular collagen deposition and hypertension. Activation of nuclear factor-κB in vascular smooth muscle cells involves a complex interplay between the angiotensin subtype 1 (AT1) receptor and the mineralocorticoid receptor. Activation of the mineralocorticoid receptor by aldosterone stimulates an inflammatory phenotype in adipocytes and contributes to insulin resistance by increasing oxidative stress. Summary: Mechanistic studies of aldosterone-induced inflammation provide the rationale for an expanded therapeutic role for mineralocorticoid receptor antagonists and aldosterone synthase inhibitors.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXltFKgtL4%253D&md5=4ca1eb557c5c050834bf263277edfd00

     
337. 337

     Fujisawa, G.; Muto, S.; Okada, K.; Kusano, E.; Ishibashi, S. Mineralocorticoid Receptor Antagonist Spironolactone Prevents Pig Serum-Induced Hepatic Fibrosis in Rats. Transl. Res. 2006, 148, 149– 156,  DOI: 10.1016/j.trsl.2006.03.007

     [Crossref], [PubMed], [CAS], Google Scholar

     337

     Mineralocorticoid receptor antagonist spironolactone prevents pig serum-induced hepatic fibrosis in rats

     Fujisawa, Genro; Muto, Shigeaki; Okada, Koji; Kusano, Eiji; Ishibashi, Shun

     Translational Research (2006), 148 (3), 149-156CODEN: TRRECL; ISSN:1931-5244. (Elsevier)

     Mineralocorticoid receptor (MR) antagonist spironolactone (SPL) is an effective agent for prevention of cardiovascular injury. However, whether and how SPL ameliorates hepatic fibrosis in rats is unknown. Pig serum (PS) (0.5 mL, twice a week, i.p.) or vehicle-administered rats for 12 wk were used as rats with hepatic fibrosis or control rats, resp. Rats given PS were treated with SPL (50 mg/kg/day, s.c.) for 12 wk. Hepatic fibrosis, using picro-sirius red staining and detn. of hydroxyproline content, immunohistochemistries of α-smooth muscle actin (α-SMA)-pos. hepatic stellate cells (HSCs), Na/H exchange isoform-1 (NHE-1) protein, CYP11B2 aldosterone synthase protein for liver tissues, and plasma aldosterone concns. were compared among the 3 groups of rats. Rats given PS alone exhibited hepatic fibrosis as well as increases in the no. of the α-SMA-pos. HSCs and NHE-1 protein expression in HSCs and hepatocytes, all of which were suppressed by SPL. Rats given PS alone revealed increased CYP11B2 protein expression in HSCs and hepatocytes, which was not inhibited by SPL. Plasma aldosterone concns. were significantly greater in rats given PS and SPL than in control rats and rats given PS alone, although they were not different between control rats and rats given PS alone. PS-induced hepatic fibrosis together with HSC activation and NHE-1 protein expression occurs via MRs, and SPL ameliorates hepatic fibrosis presumably via the inhibition of HSC activation and NHE-1 protein expression in PS-induced liver injuries. The aldosterone produced in the injured liver contributes to the PS-induced hepatic fibrosis.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XhtFWjsrrP&md5=b3e191f1e5a1bbcd41decb2da5c945bb

     
338. 338

     de Gasparo, M.; Joss, U.; Ramjoue, H. P.; Whitebread, S. E.; Haenni, H.; Schenkel, L.; Kraehenbuehl, C.; Biollaz, M.; Grob, J.; Schmidlin, J.; Wieland, P.; Wehrli, H. U. Three New Epoxy-Spirolactone Derivatives: Characterization In Vivo and In Vitro. J. Pharmacol. Exp. Ther. 1987, 240, 650– 656

     [PubMed], [CAS], Google Scholar

     338

     Three new epoxyspirolactone derivatives: characterization in vivo and in vitro

     De Gasparo, M.; Joss, U.; Ramjoue, H. P.; Whitebread, S. E.; Haenni, H.; Schenkel, L.; Kraehenbuehl, C.; Biollaz, M.; Grob, J.; et al.

     Journal of Pharmacology and Experimental Therapeutics (1987), 240 (2), 650-6CODEN: JPETAB; ISSN:0022-3565.

     Three 9α,11α-epoxy-derivs. of known aldosterone antagonists, I [104004-85-5], II [95716-94-2], and III [107724-20-9], were characterized in vitro and in vivo. In each expt. spironolactone was run as a ref. The introduction of the epoxy-group only marginally affected the binding affinity of these compds. for the mineralocorticoid receptor, whereas it caused a decrease for the androgen and progesterone receptors of 10-500-fold. In vivo, all 3 epoxy-derivs. (3 mg/kg) were potent aldosterone antagonists, with 1-2 times the potency of spironolactone in the rat. Parallel to the decreased affinity for the androgen and progesterone receptor in vitro, there was a 3-10-fold decrease of the antiandrogenic and progestogenic effect compared to spironolactone in the rat and in the rabbit, resp. Virtually no disturbance of the vaginal or ovulatory cycle was obsd. with either II or III, although I caused a 20% decrease in ovulation. Apparently, the 9α,11α-position of the steroid structure is a site of the mol. which can be modified to improve the specificity of aldosterone antagonists not only in vitro, but also in vivo.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL2sXhs12hsLw%253D&md5=77d1b849e290f4112e39a72506e2c3f3

     
339. 339

     Wada, T.; Miyashita, Y.; Sasaki, M.; Aruga, Y.; Nakamura, Y.; Ishii, Y.; Sasahara, M.; Kanasaki, K.; Kitada, M.; Koya, D.; Shimano, H.; Tsuneki, H.; Sasaoka, T. Eplerenone Ameliorates the Phenotypes of Metabolic Syndrome with NASH in Liver-Specific SREBP-1c Tg Mice Fed High-Fat and High-Fructose Diet. Am. J. Physiol. Endocrinol. Metab. 2013, 305, E1415– 1425,  DOI: 10.1152/ajpendo.00419.2013

     [Crossref], [PubMed], Google Scholar

     There is no corresponding record for this reference.

     
340. 340

     Pizarro, M.; Solis, N.; Quintero, P.; Barrera, F.; Cabrera, D.; Rojas-de Santiago, P.; Arab, J. P.; Padilla, O.; Roa, J. C.; Moshage, H.; Wree, A.; Inzaugarat, E.; Feldstein, A. E.; Fardella, C. E.; Baudrand, R.; Riquelme, A.; Arrese, M. Beneficial Effects of Mineralocorticoid Receptor Blockade in Experimental Non-Alcoholic Steatohepatitis. Liver Int. 2015, 35, 2129– 2138,  DOI: 10.1111/liv.12794

     [Crossref], [PubMed], [CAS], Google Scholar

     340

     Beneficial effects of mineralocorticoid receptor blockade in experimental non-alcoholic steatohepatitis

     Pizarro, Margarita; Solis, Nancy; Quintero, Pablo; Barrera, Francisco; Cabrera, Daniel; Rojas-de Santiago, Pamela; Arab, Juan P.; Padilla, Oslando; Roa, Juan C.; Moshage, Han; Wree, Alexander; Inzaugarat, Eugenia; Feldstein, Ariel E.; Fardella, Carlos E.; Baudrand, Rene; Riquelme, Arnoldo; Arrese, Marco

     Liver International (2015), 35 (9), 2129-2138CODEN: LIINCM; ISSN:1478-3223. (Wiley-Blackwell)

     Background : Therapeutic options to treat Non-alc. steatohepatitis (NASH) are limited. Mineralocorticoid receptor (MR) activation could play a role in hepatic fibrogenesis and its modulation could be beneficial for NASH. Aim : To investigate whether eplerenone, a specific MR antagonist, ameliorates liver damage in exptl. NASH. Methods : C57bl6 mice were fed a choline-deficient and amino acid-defined (CDAA) diet for 22 wk with or without eplerenone supplementation. Serum levels of aminotransferases and aldosterone were measured and hepatic steatosis, inflammation and fibrosis scored histol. Hepatic triglyceride content (HTC) and hepatic mRNA levels of pro-inflammatory pro-fibrotic, oxidative stress-assocd. genes and of MR were also assessed. Results : CDAA diet effectively induced fibrotic NASH, and increased the hepatic expression of pro-inflammatory, pro-fibrotic and oxidative stress-assocd. genes. Hepatic MR mRNA levels significantly correlated with the expression of pro-inflammatory and pro-fibrotic genes and were significantly increased in hepatic stellate cells obtained from CDAA-fed animals. Eplerenone administration was assocd. to a redn. in histol. steatosis and attenuation of liver fibrosis development, which was assocd. to a significant decrease in the expression of collagen-α1, collagen type III, alpha 1 and Matrix metalloproteinase-2. Conclusion : The expression of MR correlates with inflammation and fibrosis development in exptl. NASH. Specific MR blockade with eplerenone has hepatic anti-steatotic and anti-fibrotic effects. These data identify eplerenone as a potential novel therapy for NASH. Considering its safety and FDA-approved status, human studies are warranted.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtlWmtb7E&md5=a3f06de0772eb025e2ae381b1b0328ca

     
341. 341

     Iijima, T.; Yamamoto, Y.; Akatsuka, H.; Kawaguchi, T. Benzoxazines and Related Nitrogen-Containing Heterobicyclic Compounds Useful as Mineralocorticoid Receptor Modulating Agents. International Patent WO2007089034, 2007.

     Google Scholar

     There is no corresponding record for this reference.

     
342. 342

     Jaakkola, K.; Kaunismaki, K.; Tohka, S.; Yegutkin, G.; Vanttinen, E.; Havia, T.; Pelliniemi, L. J.; Virolainen, M.; Jalkanen, S.; Salmi, M. Human Vascular Adhesion Protein-1 in Smooth Muscle Cells. Am. J. Pathol. 1999, 155, 1953– 1965,  DOI: 10.1016/S0002-9440(10)65514-9

     [Crossref], [PubMed], [CAS], Google Scholar

     342

     Human vascular adhesion protein-1 in smooth muscle cells

     Jaakkola, Kimmo; Kaunismaki, Katja; Tohka, Sami; Yegutkin, Gennady; Vanttinen, Esko; Havia, Tapani; Pelliniemi, Lauri J.; Virolainen, Martti; Jalkanen, Sirpa; Salmi, Marko

     American Journal of Pathology (1999), 155 (6), 1953-1965CODEN: AJPAA4; ISSN:0002-9440. (American Society for Investigative Pathology)

     Human vascular adhesion protein-1 (VAP-1) is a dual-function mol. with adhesive and enzymic properties. In addn. to synthesis in endothelial cells, where it mediates lymphocyte binding, VAP-1 is expressed in smooth muscle cells. Here, the authors studied the expression, biochem. structure, and function of VAP-1 in muscle cells and compared it to those in endothelial cells. VAP-1 was expressed on the plasma membrane of all types of smooth muscle cells, but it was completely absent from cardiac and skeletal muscle cells. In tumors, VAP-1 was retained on all leiomyoma cells, whereas it was lost in half of leiomyosarcoma samples. In smooth muscle, VAP-1 was found to exist predominantly as a ∼165-kDa homodimeric glycoprotein, but a trimeric (∼250 kDa) form of VAP-1 was also found. It contained N-linked oligosaccharide side-chains and abundant sialic acid decorations. In comparison, in endothelial cells dimeric VAP-1 was larger, no trimeric forms were found, and VAP-1 did not have N-glycanase-sensitive oligosaccharides. Unlike endothelial VAP-1, VAP-1 localized on smooth muscle cells did not support binding of lymphocytes. Instead, it deaminated exogenous and endogenous primary amines. In conclusion, VAP-1 in smooth muscle cells is structurally and functionally distinct from VAP-1 present on endothelial cells.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXit1Kgsw%253D%253D&md5=7532abde0d251184ee349cae0d42535f

     
343. 343

     Salmi, M.; Kalimo, K.; Jalkanen, S. Induction and Function of Vascular Adhesion Protein-1 at Sites of Inflammation. J. Exp. Med. 1993, 178, 2255– 2260,  DOI: 10.1084/jem.178.6.2255

     [Crossref], [PubMed], [CAS], Google Scholar

     343

     Induction and function of vascular adhesion protein-1 at sites of inflammation

     Salmi, Marko; Kalimo, Kirsti; Jalkanen, Sirpa

     Journal of Experimental Medicine (1993), 178 (6), 2255-60CODEN: JEMEAV; ISSN:0022-1007.

     Emigration of leukocytes from the blood into the tissues is crit. in controlling lymphocyte patrolling in different lymphatic organs and in leukocyte accumulation at sites of inflammation. During the first stage of the extravasation process, leukocytes bind to the endothelial lining of vessels. At the mol. level, several adhesion mols. on leukocytes and endothelial cells function as receptor-ligand pairs in mediating this dynamic interaction. Recently, the authors have identified a novel human endothelial cell mol., vascular adhesion protein 1 (VAP-1), that mediates lymphocyte binding (Salmi, M.; Jalkanen, S., 1992). VAP-1 was initially characterized by monoclonal antibody (mAb) 1B2 which inhibits lymphocyte adhesion to high endothelial venules (HEV) and to purified VAP-1 protein. Here the authors report the location and function of VAP-1 in normal and inflamed tissues in humans. VAP-1 is abundant in HEV of lymphatic organs belonging to the peripheral lymph node system, but considerably less expressed in vessels of mucosa-assocd. lymphatic tissues. A subset of venules in most normal nonlymphatic tissues such as skin, brain, kidney, liver, and heart is also VAP-1 pos. In addn. to vessels, VAP-1 is distributed on a few other cell types, most notably in dendritic-like cells of germinal centers. At sites of inflammation, such as in inflammatory bowel diseases and chronic dermatoses, expression of VAP-1 is clearly increased. The induced VAP-1 is functional, since mAb 1B2 inhibits lymphocyte binding to inflamed lamina propria venules by ∼60%. Thus VAP-1 is an endothelial adhesion mol. that under normal conditions is expressed mainly in HEV of lymphatic tissues. However, expression of functional VAP-1 in vivo is upregulated during an inflammatory reaction at other sites as well. Inducibility of VAP-1 suggests that it may play a significant role, not only in recirculation of lymphocytes, but also in controlling entry of leukocytes into sites of inflammation.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3sXmt1Citro%253D&md5=3f188b4526be8936cd5761f23fdd2627

     
344. 344

     Salmi, M.; Jalkanen, S. A 90-Kilodalton Endothelial Cell Molecule Mediating Lymphocyte Binding in Humans. Science 1992, 257, 1407– 1409,  DOI: 10.1126/science.1529341

     [Crossref], [PubMed], [CAS], Google Scholar

     344

     A 90-kilodalton endothelial cell molecule mediating lymphocyte binding in humans

     Salmi, Marko; Jalkanen, Sirpa

     Science (Washington, DC, United States) (1992), 257 (5075), 1407-9CODEN: SCIEAS; ISSN:0036-8075.

     A heretofore undescribed 90-kilodalton human endothelial cell adhesion mol. (VAP-1) defined by a monoclonal antibody 1B2 is described. The expression pattern, mol. mass, functional properties, and an N-terminal amino acid sequence define VAP-1 as an endothelial ligand for lymphocytes. VAP-1 helps to elucidate the complex heterotypic cell interactions that direct tissue-selective lymphocyte migration in man.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK38XmtlSksL0%253D&md5=8ed0c3c53ae1d56516101f3d3cc77ed8

     
345. 345

     Abella, A.; Garcia-Vicente, S.; Viguerie, N.; Ros-Baro, A.; Camps, M.; Palacin, M.; Zorzano, A.; Marti, L. Adipocytes Release a Soluble Form of VAP-1/SSAO by a Metalloprotease-Dependent Process and in a Regulated Manner. Diabetologia 2004, 47, 429– 438,  DOI: 10.1007/s00125-004-1346-2

     [Crossref], [PubMed], [CAS], Google Scholar

     345

     Adipocytes release a soluble form of VAP-1/SSAO by a metalloprotease-dependent process and in a regulated manner

     Abella, A.; Garcia-Vicente, S.; Viguerie, N.; Ros-Baro, A.; Camps, M.; Palacin, M.; Zorzano, A.; Marti, L.

     Diabetologia (2004), 47 (3), 429-438CODEN: DBTGAJ; ISSN:0012-186X. (Springer-Verlag)

     Vascular adhesion protein-1 (VAP-1), which is identical to semicarbazide-sensitive amine oxidase (SSAO), is a dual-function membrane protein with adhesion properties and amine oxidase activity. A sol. form of VAP-1 is found in serum, where concns. are enhanced in diabetes and obesity. In vitro, sol. VAP-1 enhances lymphocyte adhesion to endothelial cells, thus possibly participating in the enhanced lymphocyte adhesion capacity that is implicated in the cardiovascular complications assocd. with diabetes or obesity. In both, the tissue origin of the sol. VAP-1/SSAO is unknown. The authors examd. whether adipose tissue, which has abundant expression of VAP-1/SSAO, is a source of sol. VAP-1. Methods. The authors detected VAP-1/SSAO in plasma of diabetic animals, with or without VAP-1 immunopptn., and in culture medium from 3T3-L1 adipocytes and human adipose tissue explants. VAP-1 protein glycosylation was measured. Diabetic and obese animals have increased plasma SSAO activity assocd. with VAP-1 protein. The authors also found that 3T3-L1 adipocytes and human adipose tissue explants release a sol. form of VAP-1/SSAO, which derives from the membrane. The release of sol. VAP-1 was enhanced by exposure of murine and human adipocytes to TNF-α and blocked by batimastat, a metalloprotease inhibitor. Partial ablation of adipose tissue reduced plasma SSAO activity in normal and diabetic rats. Adipose cells are a source of sol. VAP-1/SSAO released by shedding of the membrane form. The release of SSAO is regulated by TNF-α and insulin. By releasing VAP-1/SSAO, adipose cells could contribute to the atherogenesis and vascular dysfunction assocd. with diabetes and obesity.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXis1Ggtr0%253D&md5=5988aefc036b0212cbc1bd8f5ee04c1e

     
346. 346

     Li, H. Y.; Lin, M. S.; Wei, J. N.; Hung, C. S.; Chiang, F. T.; Lin, C. H.; Hsu, H. C.; Su, C. Y.; Wu, M. Y.; Smith, D. J.; Vainio, J.; Chen, M. F.; Chuang, L. M. Change of Serum Vascular Adhesion Protein-1 after Glucose Loading Correlates to Carotid Intima-Medial Thickness in Non-Diabetic Subjects. Clin. Chim. Acta 2009, 403, 97– 101,  DOI: 10.1016/j.cca.2009.01.027

     [Crossref], [PubMed], [CAS], Google Scholar

     346

     Change of serum vascular adhesion protein-1 after glucose loading correlates to carotid intima-medial thickness in non-diabetic subjects

     Li, Hung-Yuan; Lin, Mao-Shin; Wei, Jung-Nan; Hung, Chi Sheng; Chiang, Fu-Tien; Lin, Cheng-Hsin; Hsu, Hsiu-Ching; Su, Chien-Yin; Wu, Mei-Yu; Smith, David J.; Vainio, Jani; Chen, Ming-Fong; Chuang, Lee-Ming

     Clinica Chimica Acta (2009), 403 (1-2), 97-101CODEN: CCATAR; ISSN:0009-8981. (Elsevier B.V.)

     We investigated if serum vascular adhesion protein-1 (SSAO/VAP-1) changed acutely following oral glucose loading and whether such changes are correlated with surrogate markers of atherosclerosis. A total of 115 non-diabetics subjects were enrolled for an oral glucose tolerance test (OGTT). Carotid intima-medial thickness (IMT) was measured by ultrasonog. Serum SSAO/VAP-1 was analyzed by time-resolved immunofluorometric assay. Serum thiobarbituric acid reactive substances (TBARS) and advanced glycated end products (AGEs) were measured by fluorometric assays. Serum SSAO/VAP-1 increased significantly at 30 min after oral glucose loading and lasted to 2 h (p = 0.0005 and p < 0.0001, for 30 min and 2 h resp.). The area under curve of serum SSAO/VAP-1 during OGTT (AUC-VAP-1) correlated significantly with carotid IMT, independent of age, gender, low-d. lipoprotein cholesterol, systolic blood pressure, Hb A1c, serum TBARS, AGEs, and high-sensitivity C-reactive protein. Subjects with a pos. AUC-VAP-1 had significantly higher serum TBARS and AGEs than subjects with a neg. AUC-VAP-1 adjusted for age and gender. Serum SSAO/VAP-1 changed acutely following oral glucose loading in non-diabetic subjects. Change of serum SSAO/VAP-1 correlated independently to serum TBARS, AGEs, and carotid IMT. Our findings suggest that acute change of serum SSAO/VAP-1 is a novel marker for hyperglycemia-induced atherosclerosis.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXltFWmt7c%253D&md5=6ee89ad2d86c1bab4ac65e2b62e84af4

     
347. 347

     Pannecoeck, R.; Serruys, D.; Benmeridja, L.; Delanghe, J. R.; van Geel, N.; Speeckaert, R.; Speeckaert, M. M. Vascular Adhesion Protein-1: Role in Human Pathology and Application as a Biomarker. Crit. Rev. Clin. Lab. Sci. 2015, 52, 284– 300,  DOI: 10.3109/10408363.2015.1050714

     [Crossref], [PubMed], [CAS], Google Scholar

     347

     Vascular adhesion protein-1: Role in human pathology and application as a biomarker

     Pannecoeck, Roos; Serruys, Daphne; Benmeridja, Lara; Delanghe, Joris R.; Geel, Nanja van; Speeckaert, Reinhart; Speeckaert, Marijn M.

     Critical Reviews in Clinical Laboratory Sciences (2015), 52 (6), 284-300CODEN: CRCLBH; ISSN:1040-8363. (Taylor & Francis Ltd.)

     A review. Vascular adhesion protein-1 (VAP-1) is a member of the copper-contg. amine oxidase/semicarbazide-sensitive amine oxidase (AOC/SSAO) enzyme family. SSAO enzymes catalyze oxidative deamination of primary amines, which results in the prodn. of the corresponding aldehyde, hydrogen peroxide and ammonium. VAP-1 is continuously expressed as a transmembrane glycoprotein in the vascular wall during development and facilitates the accumulation of inflammatory cells into the inflamed environment in concert with other leukocyte adhesion mols. The sol. form of VAP-1 is released into the circulation mainly from vascular endothelial cells. Over- and under-expression of sVAP-1 result in alterations of the reported reaction product levels, which are involved in the pathogenesis of multiple human diseases. The combination of enzymic and adhesion capacities as well as its strong assocn. with inflammatory pathologies makes VAP-1 an interesting therapeutic target for drug discovery. In this article, we will review the general characteristics and biol. functions of VAP-1, focusing on its important role as a prognostic biomarker in human pathologies. In addn., the potential therapeutic application of VAP-1 inhibitors will be discussed.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsl2nur%252FI&md5=5a4860753e9736063657ebf95145823e

     
348. 348

     Salmi, M.; Jalkanen, S. Vascular Adhesion Protein-1: A Cell Surface Amine Oxidase in Translation. Antioxid. Redox Signaling 2019, 30, 314– 332,  DOI: 10.1089/ars.2017.7418

     [Crossref], [PubMed], [CAS], Google Scholar

     348

     Vascular Adhesion Protein-1: A Cell Surface Amine Oxidase in Translation

     Salmi, Marko; Jalkanen, Sirpa

     Antioxidants & Redox Signaling (2019), 30 (3), 314-332CODEN: ARSIF2; ISSN:1523-0864. (Mary Ann Liebert, Inc.)

     Significance: Vascular adhesion protein-1 (VAP-1) is an ectoenzyme that oxidates primary amines in a reaction producing also hydrogen peroxide. VAP-1 on the blood vessel endothelium regulates leukocyte extravasation from the blood into tissues under physiol. and pathol. conditions. Recent Advances: Inhibition of VAP-1 by neutralizing antibodies and by several novel small-mol. enzyme inhibitors interferes with leukocyte trafficking and alleviates inflammation in many exptl. models. Targeting of VAP-1 also shows beneficial effects in several other diseases, such as ischemia/reperfusion, fibrosis, and cancer. Moreover, sol. VAP-1 levels may serve as a new prognostic biomarker in selected diseases. Crit. Issues: Understanding the contribution of the enzyme activity-independent and enzyme activity-dependent functions, which often appear to be mediated by the hydrogen peroxide prodn., in the VAP-1 biol. will be crucial. Similarly, there is a pressing need to understand which of the VAP-1 functions are regulated through the modulation of leukocyte trafficking, and what is the role of VAP-1 synthesized in adipose and smooth muscle cells. Future Directions: The specificity and selectivity of new VAP-1 inhibitors, and their value in animal models under therapeutic settings need to be addressed. Results from several programs studying the therapeutic potential of VAP-1 inhibition, which now are in clin. trials, will reveal the relevance of this amine oxidase in humans.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXisFSmsrjM&md5=5fe646b1e851f3e4e2c25e14cb32dec7

     
349. 349

     Weston, C. J.; Shepherd, E. L.; Claridge, L. C.; Rantakari, P.; Curbishley, S. M.; Tomlinson, J. W.; Hubscher, S. G.; Reynolds, G. M.; Aalto, K.; Anstee, Q. M.; Jalkanen, S.; Salmi, M.; Smith, D. J.; Day, C. P.; Adams, D. H. Vascular Adhesion Protein-1 Promotes Liver Inflammation and Drives Hepatic Fibrosis. J. Clin. Invest. 2015, 125, 501– 520,  DOI: 10.1172/JCI73722

     [Crossref], [PubMed], [CAS], Google Scholar

     349

     Vascular adhesion protein-1 promotes liver inflammation and drives hepatic fibrosis

     Weston Chris J; Shepherd Emma L; Claridge Lee C; Rantakari Pia; Curbishley Stuart M; Tomlinson Jeremy W; Hubscher Stefan G; Reynolds Gary M; Aalto Kristiina; Anstee Quentin M; Jalkanen Sirpa; Salmi Marko; Smith David J; Day Christopher P; Adams David H

     The Journal of clinical investigation (2015), 125 (2), 501-20 ISSN:.

     Nonalcoholic fatty liver disease (NAFLD) encompasses a range of manifestations, including steatosis and cirrhosis. Progressive disease is characterized by hepatic leukocyte accumulation in the form of steatohepatitis. The adhesion molecule vascular adhesion protein-1 (VAP-1) is a membrane-bound amine oxidase that promotes leukocyte recruitment to the liver, and the soluble form (sVAP-1) accounts for most circulating monoamine oxidase activity, has insulin-like effects, and can initiate oxidative stress. Here, we determined that hepatic VAP-1 expression is increased in patients with chronic liver disease and that serum sVAP-1 levels are elevated in patients with NAFLD compared with those in control individuals. In 4 murine hepatic injury models, an absence or blockade of functional VAP-1 reduced inflammatory cell recruitment to the liver and attenuated fibrosis. Moreover, disease was reduced in animals expressing a catalytically inactive form of VAP-1, implicating enzyme activity in the disease pathogenesis. Within the liver, hepatic stromal cells expressed functional VAP-1, and evaluation of cultured cells revealed that sVAP-1 promotes leukocyte migration through catalytic generation of ROS, which depended on VAP-1 enzyme activity. VAP-1 enhanced stromal cell spreading and wound closure and modulated expression of profibrotic genes. Together, these results link the amine oxidase activity of VAP-1 with hepatic inflammation and fibrosis and suggest that targeting VAP-1 has therapeutic potential for NAFLD and other chronic fibrotic liver diseases.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2MvjslyhtA%253D%253D&md5=391afbe136ea913db55950f924936961

     
350. 350

     Dunkel, P.; Balogh, B.; Meleddu, R.; Maccioni, E.; Gyires, K.; Matyus, P. Semicarbazide-Sensitive Amine Oxidase/Vascular Adhesion Protein-1: A Patent Survey. Expert Opin. Ther. Pat. 2011, 21, 1453– 1471,  DOI: 10.1517/13543776.2011.594040

     [Crossref], [PubMed], [CAS], Google Scholar

     350

     Semicarbazide-sensitive amine oxidase/vascular adhesion protein-1: a patent survey

     Dunkel, Petra; Balogh, Balazs; Meleddu, Rita; Maccioni, Elias; Gyires, Klara; Matyus, Peter

     Expert Opinion on Therapeutic Patents (2011), 21 (9), 1453-1471CODEN: EOTPEG; ISSN:1354-3776. (Informa Healthcare)

     A review. Vascular adhesion protein-1 (VAP-1)/semicarbazide-sensitive amine oxidase (SSAO) is an adhesion protein involved in leukocyte trafficking and inflammatory processes, with a special amine oxidase activity. Inhibitors have been mainly developed for treating chronic inflammatory disorders. The utility of inhibitors as antiangiogenic agents in ophthalmol. and oncol. diseases is currently under evaluation. SSAO substrates may mimic several insulin effects, although their utility for the treatment of diabetes is still far from being fully understood.Areas covered: This paper reviews the patent literature of SSAO/VAP-1 inhibitors and substrates, for the period of 1990-2010. The current stage of SSAO/VAP-1-interacting agents published in patents is described, along with their chem. structures and pharmacol. uses.Expert opinion: SSAO/VAP-1 is a promising anti-inflammatory target. Another important field for therapeutic application of these inhibitors may be ophthalmol., due to their antiangiogenic effects. SSAO substrates might also be of therapeutic value in the treatment of diabetes; however, more extensive research has to be undertaken to validate this approach.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtVWnu77M&md5=4f90f6b6bcae20f6c56636b28c4b561a

     
351. 351

     Schilter, H. C.; Collison, A.; Russo, R. C.; Foot, J. S.; Yow, T. T.; Vieira, A. T.; Tavares, L. D.; Mattes, J.; Teixeira, M. M.; Jarolimek, W. Effects of an Anti-Inflammatory VAP-1/SSAO Inhibitor, PXS-4728A, on Pulmonary Neutrophil Migration. Respir. Res. 2015, 16, 42,  DOI: 10.1186/s12931-015-0200-z

     [Crossref], [PubMed], [CAS], Google Scholar

     351

     Effects of an anti-inflammatory VAP-1/SSAO inhibitor, PXS-4728A, on pulmonary neutrophil migration

     Schilter Heidi C; Foot Jonathan S; Yow Tin T; Jarolimek Wolfgang; Collison Adam; Mattes Joerg; Russo Remo C; Russo Remo C; Vieira Angelica T; Tavares Livia D; Teixeira Mauro M; Jarolimek Wolfgang

     Respiratory research (2015), 16 (), 42 ISSN:.

     BACKGROUND AND PURPOSE: The persistent influx of neutrophils into the lung and subsequent tissue damage are characteristics of COPD, cystic fibrosis and acute lung inflammation. VAP-1/SSAO is an endothelial bound adhesion molecule with amine oxidase activity that is reported to be involved in neutrophil egress from the microvasculature during inflammation. This study explored the role of VAP-1/SSAO in neutrophilic lung mediated diseases and examined the therapeutic potential of the selective inhibitor PXS-4728A. METHODS: Mice treated with PXS-4728A underwent intra-vital microscopy visualization of the cremaster muscle upon CXCL1/KC stimulation. LPS inflammation, Klebsiella pneumoniae infection, cecal ligation and puncture as well as rhinovirus exacerbated asthma models were also assessed using PXS-4728A. RESULTS: Selective VAP-1/SSAO inhibition by PXS-4728A diminished leukocyte rolling and adherence induced by CXCL1/KC. Inhibition of VAP-1/SSAO also dampened the migration of neutrophils to the lungs in response to LPS, Klebsiella pneumoniae lung infection and CLP induced sepsis; whilst still allowing for normal neutrophil defense function, resulting in increased survival. The functional effects of this inhibition were demonstrated in the RV exacerbated asthma model, with a reduction in cellular infiltrate correlating with a reduction in airways hyperractivity. CONCLUSIONS AND IMPLICATIONS: This study demonstrates that the endothelial cell ligand VAP-1/SSAO contributes to the migration of neutrophils during acute lung inflammation, pulmonary infection and airway hyperractivity. These results highlight the potential of inhibiting of VAP-1/SSAO enzymatic function, by PXS-4728A, as a novel therapeutic approach in lung diseases that are characterized by neutrophilic pattern of inflammation.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2MjlvVehug%253D%253D&md5=8a1e21dcc37596356424720fd11bcc1d

     
352. 352

     Milczek, E. M.; Bonivento, D.; Binda, C.; Mattevi, A.; McDonald, I. A.; Edmondson, D. E. Structural and Mechanistic Studies of Mofegiline Inhibition of Recombinant Human Monoamine Oxidase B. J. Med. Chem. 2008, 51, 8019– 8026,  DOI: 10.1021/jm8011867

     [ACS Full Text ], [CAS], Google Scholar

     352

     Structural and Mechanistic Studies of Mofegiline Inhibition of Recombinant Human Monoamine Oxidase B

     Milczek, Erika M.; Bonivento, Daniele; Binda, Claudia; Mattevi, Andrea; McDonald, Ian A.; Edmondson, Dale E.

     Journal of Medicinal Chemistry (2008), 51 (24), 8019-8026CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

     Mechanistic and structural studies have been carried out to investigate the mol. basis for the irreversible inhibition of human MAO-B by mofegiline. Competitive inhibition with substrate shows an apparent Ki of 28 nM. Irreversible inhibition of MAO-B occurs with a 1:1 M stoichiometry with no observable catalytic turnover. The absorption spectral properties of mofegiline inhibited MAO-B show features (λmax ≃ 450 nm) unlike those of traditional flavin N(5) or C(4a) adducts. Visible and near-UV CD spectra of the mofegiline-MAO-B adduct shows a neg. peak at 340 nm with an intensity similar to that of N(5) flavocyanine adducts. The x-ray crystal structure of the mofegiline-MAO-B adduct shows a covalent bond between the flavin cofactor N(5) with the distal allylamine carbon atom as well as the absence of the fluorine atom. A mechanism to explain these structural and spectral data is proposed.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhsVKlu73L&md5=a2155647066b1e971ecc2b7680ee7bee

     
353. 353

     Foot, J. S.; Deodhar, M.; Turner, C. I.; Yin, P.; van Dam, E. M.; Silva, D. G.; Olivieri, A.; Holt, A.; McDonald, I. A. The Discovery and Development of Selective 3-Fluoro-4-Aryloxyallylamine Inhibitors of the Amine Oxidase Activity of Semicarbazide-Sensitive Amine Oxidase/Vascular Adhesion Protein-1 (SSAO/VAP-1). Bioorg. Med. Chem. Lett. 2012, 22, 3935– 3940,  DOI: 10.1016/j.bmcl.2012.04.111

     [Crossref], [PubMed], [CAS], Google Scholar

     353

     The discovery and development of selective 3-fluoro-4-aryloxyallylamine inhibitors of the amine oxidase activity of semicarbazide-sensitive amine oxidase/vascular adhesion protein-1 (SSAO/VAP-1)

     Foot, Jonathan S.; Deodhar, Mandar; Turner, Craig I.; Yin, Ping; van Dam, Ellen M.; Silva, Diego G.; Olivieri, Aldo; Holt, Andrew; McDonald, Ian A.

     Bioorganic & Medicinal Chemistry Letters (2012), 22 (12), 3935-3940CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)

     A new class of 3-fluoroallyl amine-based SSAO/VAP-1 inhibitors is reported. These compds. have excellent selectivity over diamine oxidase, MAO-A and MAO-B. Synthesis and SAR studies leading to compd. 28 (PXS-4159A, I) are reported. The pharmacokinetic profile of 28 in the rat, together with activity in a murine model of lung inflammation are also disclosed.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XntVyrtLg%253D&md5=cb02b80379ec2a2a6323b158f2297944

     
354. 354

     Foot, J. S.; Yow, T. T.; Schilter, H.; Buson, A.; Deodhar, M.; Findlay, A. D.; Guo, L.; McDonald, I. A.; Turner, C. I.; Zhou, W.; Jarolimek, W. PXS-4681A, a Potent and Selective Mechanism-Based Inhibitor of SSAO/VAP-1 with Anti-Inflammatory Effects In Vivo. J. Pharmacol. Exp. Ther. 2013, 347, 365– 374,  DOI: 10.1124/jpet.113.207613

     [Crossref], [PubMed], [CAS], Google Scholar

     354

     PXS-4681A, a potent and selective mechanism-based inhibitor of SSAO/VAP-1 with anti-inflammatory effects in vivo

     Foot, Jonathan S.; Yow, Tin T.; Schilter, Heidi; Buson, Alberto; Deodhar, Mandar; Findlay, Alison D.; Guo, Lily; McDonald, Ian A.; Turner, Craig I.; Zhou, Wenbin; Jarolimek, Wolfgang

     Journal of Pharmacology and Experimental Therapeutics (2013), 347 (2), 365-374CODEN: JPETAB; ISSN:1521-0103. (American Society for Pharmacology and Experimental Therapeutics)

     Semicarbazide-sensitive amine oxidase (SSAO), also known as vascular adhesion protein-1 (VAP-1), is a member of the copper-dependent amine oxidase family that is assocd. with various forms of inflammation and fibrosis. To investigate the therapeutic potential of SSAO/VAP-1 inhibition, potent and selective inhibitors with drug-like properties are required. PXS-4681A [(Z)-4-(2-(aminomethyl)-3-fluoroallyloxy)benzenesulfonamide hydrochloride] is a mechanism-based inhibitor of enzyme function with a pharmacokinetic and pharmacodynamic profile that ensures complete, long-lasting inhibition of the enzyme after a single low dose in vivo. PXS-4681A irreversibly inhibits the enzyme with an apparent Ki of 37 nM and a kinact of 0.26 min-1 with no obsd. turnover in vitro. It is highly selective for SSAO/VAP-1 when profiled against related amine oxidases, ion channels, and seven-transmembrane domain receptors, and is superior to previously reported inhibitors. In mouse models of lung inflammation and localized inflammation, dosing of this mol. at 2 mg/kg attenuates neutrophil migration, tumor necrosis factor-α, and interleukin-6 levels. These results demonstrate the drug-like properties of PXS-4681A and its potential use in the treatment of inflammation.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhslSqsL3L&md5=d3c24925c4b717c9405d46be9a82f2d9

     
355. 355

     Wang, S. H.; Yu, T. Y.; Hung, C. S.; Yang, C. Y.; Lin, M. S.; Su, C. Y.; Chen, Y. L.; Kao, H. L.; Chuang, L. M.; Tsai, F. C.; Li, H. Y. Inhibition of Semicarbazide-sensitive Amine Oxidase Reduces Atherosclerosis in Cholesterol-fed New Zealand White Rabbits. Sci. Rep. 2018, 8, 9249,  DOI: 10.1038/s41598-018-27551-6

     [Crossref], [PubMed], [CAS], Google Scholar

     355

     Inhibition of Semicarbazide-sensitive Amine Oxidase Reduces Atherosclerosis in Cholesterol-fed New Zealand White Rabbits

     Wang Shu-Huei; Chen Yuh-Lien; Yu Tse-Ya; Hung Chi-Sheng; Lin Mao-Shin; Su Chien-Yin; Kao Hsien-Li; Chuang Lee-Ming; Tsai Feng-Chiao; Li Hung-Yuan; Yang Chung-Yi; Yang Chung-Yi; Tsai Feng-Chiao

     Scientific reports (2018), 8 (1), 9249 ISSN:.

     Inflammation, oxidative stress, and the formation of advanced glycated end-products (AGEs) are important components of atherosclerosis. Vascular adhesion protein-1 (VAP-1) participates in inflammation. Its enzymatic activity, semicarbazide-sensitive amine oxidase (SSAO), can catalyze oxidative deamination reactions to produce hydrogen peroxide and aldehydes, leading to the subsequent generation of AGEs. This study aimed to investigate the effect of VAP-1/SSAO inhibition on atherosclerosis. In our study, immunohistochemical staining showed that atherosclerotic plaques displayed higher VAP-1 expression than normal arterial walls in apolipoprotein E-deficient mice, cholesterol-fed New Zealand White rabbits and humans. In cholesterol-fed rabbits, VAP-1 was expressed on endothelial cells and smooth muscle cells in the thickened intima of the aorta. Treatment with PXS-4728A, a selective VAP-1/SSAO inhibitor, in cholesterol-fed rabbits significantly decreased SSAO-specific hydrogen peroxide generation in the aorta and reduced atherosclerotic plaques. VAP-1/SSAO inhibition also lowered blood low-density lipoprotein cholesterol, reduced the expression of adhesion molecules and inflammatory cytokines, suppressed recruitment and activation of macrophages, and decreased migration and proliferation of SMC. In conclusion, VAP-1/SSAO inhibition reduces atherosclerosis and may act through suppression of several important mechanisms for atherosclerosis.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1Mbos1Slsw%253D%253D&md5=538efd98330c2d2f6043ccd3d89c1b57

     
356. 356

     Wang, S. H.; Yu, T. Y.; Tsai, F. C.; Weston, C. J.; Lin, M. S.; Hung, C. S.; Kao, H. L.; Li, Y. I.; Sole, M.; Unzeta, M.; Chen, Y. L.; Chuang, L. M.; Li, H. Y. Inhibition of Semicarbazide-Sensitive Amine Oxidase Reduces Atherosclerosis in Apolipoprotein E-Deficient Mice. Transl. Res. 2018, 197, 12– 31,  DOI: 10.1016/j.trsl.2018.03.001

     [Crossref], [PubMed], [CAS], Google Scholar

     356

     Inhibition of semicarbazide-sensitive amine oxidase reduces atherosclerosis in apolipoprotein E-deficient mice

     Wang, Shu-Huei; Yu, Tse-Ya; Tsai, Feng-Chiao; Weston, Chris J.; Lin, Mao-Shin; Hung, Chi-Sheng; Kao, Hsien-Li; Li, Yu-I.; Sole, Montse; Unzeta, Mercedes; Chen, Yuh-Lien; Chuang, Lee-Ming; Li, Hung-Yuan

     Translational Research (2018), 197 (), 12-31CODEN: TRRECL; ISSN:1878-1810. (Elsevier B.V.)

     Inflammation, oxidative stress, and formation of advanced glycated end products (AGEs) and advanced lipoxidn. end products (ALEs) are important for atherosclerosis. Vascular adhesion protein-1 (VAP-1) participates in inflammation and has semicarbazide-sensitive amine oxidase (SSAO) activity, which catalyzes oxidative deamination to produce hydrogen peroxide and aldehydes, leading to generation of AGEs and ALEs. However, the effect of VAP-1/SSAO inhibition on atherosclerosis remains controversial, and no studies used coronary angiog. to evaluate if plasma VAP-1/SSAO is a biomarker for coronary artery disease (CAD). Here, we examd. if plasma VAP-1/SSAO is a biomarker for CAD diagnosed by coronary angiog. in humans and investigated the effect of VAP-1/SSAO inhibition by a specific inhibitor PXS-4728A on atherosclerosis in cell and animal models. In the study, VAP-1/SSAO expression was increased in plaques in humans and in apolipoprotein E (ApoE)-deficient mice, and colocalized with vascular endothelial cells and smooth muscle cells (SMCs). Patients with CAD had higher plasma VAP-1/SSAO than those without CAD. Plasma VAP-1/SSAO was pos. assocd. with the extent of CAD. In ApoE-deficient mice, VAP-1/SSAO inhibition reduced atheroma and decreased oxidative stress. VAP-1/SSAO inhibition attenuated the expression of adhesion mols., chemoattractant proteins, and proinflammatory cytokines in the aorta, and suppressed monocyte adhesion and transmigration across human umbilical vein endothelial cells. Consequently, the expression of markers for macrophage recruitment and activation in plaques was decreased by VAP-1/SSAO inhibition. Besides, VAP-1/SSAO inhibition suppressed proliferation and migration of A7r5 SMC. Our data suggest that plasma VAP-1/SSAO is a novel biomarker for the presence and the extent of CAD in humans. VAP-1/SSAO inhibition by PXS-4728A is a potential treatment for atherosclerosis.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXntlCgs7Y%253D&md5=c4a4f81dee37e22f81b9a906af24ad7b

     
357. 357

     Jarnicki, A. G.; Schilter, H.; Liu, G.; Wheeldon, K.; Essilfie, A. T.; Foot, J. S.; Yow, T. T.; Jarolimek, W.; Hansbro, P. M. The Inhibitor of Semicarbazide-Sensitive Amine Oxidase, PXS-4728A, Ameliorates Key Features of Chronic Obstructive Pulmonary Disease in a Mouse Model. Br. J. Pharmacol. 2016, 173, 3161– 3175,  DOI: 10.1111/bph.13573

     [Crossref], [PubMed], [CAS], Google Scholar

     357

     A novel SSAO inhibitor PXS-4728A suppresses inflammation and fibrosis and improves lung function in experimental chronic obstructive pulmonary disease

     Jarnicki, A. G.; Schilter, H.; Liu, G.; Wheeldon, K.; Essilfie, A-T.; Foot, J. S.; Yow, T. T.; Jarolimek, W.; Hansbro, P. M.

     British Journal of Pharmacology (2016), 173 (22), 3161-3175CODEN: BJPCBM; ISSN:1476-5381. (Wiley-Blackwell)

     Background and Purpose : Chronic obstructive pulmonary disease (COPD) is a major cause of illness and death that is often induced by cigarette smoking (CS). It is characterised by pulmonary inflammation and fibrosis that impairs lung function. Existing pharmaceuticals aim to control symptoms but have low efficacy, and there are no broadly effective treatments. A potential new therapeutic target is ectoenzyme semicarbazide-sensitive mono-amine oxidase (SSAO, or vascular adhesion protein-1, VAP-1). SSAO is elevated in smokers serum, and is a pro-inflammatory enzyme that facilitates the adhesion and transmigration of leukocytes from the vasculature to sites of inflammation. Exptl. Approach : PXS-4728A has been developed as a small mol. inhibitor of SSAO. We tested its ability to suppress SSAO activity and ameliorate inflammation and hallmark features of human disease in a mouse model of CS-induced exptl. COPD. The model replicates key aspects of human COPD, including chronic airway inflammation, fibrosis and impaired lung function. Key Results : PXS-4728A treatment completely inhibited lung and systemic SSAO activity induced by acute and chronic CS exposure. Daily oral treatment inhibited airway inflammation (immune cell influx and inflammatory factors) induced by acute CS exposure. Therapeutic treatment during chronic CS-exposure, when the key features of exptl. COPD develop and progress, substantially suppressed inflammatory cell influx and fibrosis in the airways and improved lung function. Conclusions and Implications : Treatment with the SSAO small mol. inhibitor, PXS-4728A, suppresses airway inflammation and fibrosis and improves lung function in exptl. COPD. This study demonstrates the therapeutic potential of PXS-4728A for this debilitating disease.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xht12nt7bP&md5=f0d0b1edba9246169d2584d3ceabf881

     
358. 358

     Boehringer Ingelheim http://www.pharmaxis.com.au/investor-centre/news/view/boehringer-ingelheim-discontinues-development-of-bi-1467335-for-nash (accessed Dec 18, 2019).

     Google Scholar

     There is no corresponding record for this reference.

     
359. 359

     Terns Pharmaceuticals: TERN-201. https://www.ternspharma.com/8-13-19-terns-announces-positive-interim-results-from-ongoing-phase-1-clinical-trial-of-tern-201 (accessed Sept 25, 2019).

     Google Scholar

     There is no corresponding record for this reference.

     
360. 360

     Finney, J.; Moon, H. J.; Ronnebaum, T.; Lantz, M.; Mure, M. Human Copper-Dependent Amine Oxidases. Arch. Biochem. Biophys. 2014, 546, 19– 32,  DOI: 10.1016/j.abb.2013.12.022

     [Crossref], [PubMed], [CAS], Google Scholar

     360

     Human copper-dependent amine oxidases

     Finney, Joel; Moon, Hee-Jung; Ronnebaum, Trey; Lantz, Mason; Mure, Minae

     Archives of Biochemistry and Biophysics (2014), 546 (), 19-32CODEN: ABBIA4; ISSN:0003-9861. (Elsevier B.V.)

     A review. Copper amine oxidases (CAOs) are a class of enzymes that contain Cu2+ and a tyrosine-derived quinone cofactor, and catalyze the conversion of a primary amine functional group to an aldehyde, generating H2O2 and NH3 as byproducts. These enzymes can be classified into 2 non-homologous families: 2,4,5-trihydroxyphenylalanine quinone (TPQ)-dependent CAOs and the lysine tyrosylquinone (LTQ)-dependent lysyl oxidase (LOX) family of proteins. Here, the authors focus on recent developments in the field of research concerning human CAOs and the LOX family of proteins. The aberrant expression of these enzymes is linked to inflammation, fibrosis, tumor metastasis/invasion, and other diseases. Consequently, there is a crit. need to understand the functions of these proteins at the mol. level, so that strategies targeting these enzymes can be developed to combat human diseases.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXksFaisbs%253D&md5=f7ecc08c322917ac6c9bf96636b49575

     
361. 361

     Grau-Bove, X.; Ruiz-Trillo, I.; Rodriguez-Pascual, F. Origin and Evolution of Lysyl Oxidases. Sci. Rep. 2015, 5, 10568,  DOI: 10.1038/srep10568

     [Crossref], [PubMed], [CAS], Google Scholar

     361

     Origin and evolution of lysyl oxidases

     Grau-Bove Xavier; Ruiz-Trillo Inaki; Rodriguez-Pascual Fernando

     Scientific reports (2015), 5 (), 10568 ISSN:.

     Lysyl oxidases (LOX) are copper-dependent enzymes that oxidize primary amine substrates to reactive aldehydes. The best-studied role of LOX enzymes is the remodeling of the extracellular matrix (ECM) in animals by cross-linking collagens and elastin, although intracellular functions have been reported as well. Five different LOX enzymes have been identified in mammals, LOX and LOX-like (LOXL) 1 to 4, showing a highly conserved catalytic carboxy terminal domain and more divergence in the rest of the sequence. Here we have surveyed a wide selection of genomes in order to infer the evolutionary history of LOX. We identified LOX proteins not only in animals, but also in many other eukaryotes, as well as in bacteria and archaea - which reveals a pre-metazoan origin for this gene family. LOX genes expanded during metazoan evolution resulting in two superfamilies, LOXL2/L3/L4 and LOX/L1/L5. Considering the current knowledge on the function of mammalian LOX isoforms in ECM remodeling, we propose that LOXL2/L3/L4 members might have preferentially been involved in making cross-linked collagen IV-based basement membrane, whereas the diversification of LOX/L1/L5 forms contributed to chordate/vertebrate-specific ECM innovations, such as elastin and fibronectin. Our work provides a novel view on the evolution of this family of enzymes.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2MfovFyksw%253D%253D&md5=ca8f3e5364edb3e5d19742d09d78b82a

     
362. 362

     Smith-Mungo, L. I.; Kagan, H. M. Lysyl Oxidase: Properties, Regulation and Multiple Functions in Biology. Matrix Biol. 1998, 16, 387– 398,  DOI: 10.1016/S0945-053X(98)90012-9

     [Crossref], [PubMed], [CAS], Google Scholar

     362

     Lysyl oxidase: properties, regulation and multiple functions in biology

     Smith-Mungo, Lynda I.; Kagan, Herbert M.

     Matrix Biology (1998), 16 (7), 387-398CODEN: MTBOEC; ISSN:0945-053X. (Gustav Fischer Verlag)

     A review with 79 refs. Lysyl oxidase (I) is a Cu-dependent amine oxidase that plays a crit. role in the biogenesis of connective tissue matrixes by crosslinking the extracellular matrix proteins, collagen and elastin. Levels of I increase in many fibrotic diseases, while expression of the enzyme is decreased in certain diseases involving impaired Cu metab. While the 3-dimensional structure of the enzyme is not yet available, many of its physicochem. properties, its novel carbonyl cofactor, and its catalytic mechanism have been described. I is synthesized as a preproprotein, secreted as a 50-kDa, N-glycosylated proenzyme, and then proteolytically cleaved to the 32-kDa, catalytically active, mature enzyme. Within the past decade, the gene encoding I has been cloned, facilitating investigations of the regulation of expression of the enzyme in response to diverse stimuli and in numerous disease states. Transforming growth factor-β, platelet-derived growth factor, angiotensin II, retinoic acid, fibroblast growth factor, altered serum conditions, and shear stress are among the effectors or conditions that regulate I expression. New, I-like genes have also been identified and cloned, suggesting the existence of a multigene family. It has also become increasingly evident that I may have other important biol. functions in addn. to its role in the crosslinking of elastin and collagen in the extracellular matrix.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXht12itLw%253D&md5=7c4b4bf2061eca1682e8c0f5a235c2ef

     
363. 363

     Datta, A.; Scotton, C. J.; Chambers, R. C. Novel Therapeutic Approaches for Pulmonary Fibrosis. Br. J. Pharmacol. 2011, 163, 141– 172,  DOI: 10.1111/j.1476-5381.2011.01247.x

     [Crossref], [PubMed], [CAS], Google Scholar

     363

     Novel therapeutic approaches for pulmonary fibrosis

     Datta, Arnab; Scotton, Chris J.; Chambers, Rachel C.

     British Journal of Pharmacology (2011), 163 (1), 141-172CODEN: BJPCBM; ISSN:1476-5381. (Wiley-Blackwell)

     A review. Pulmonary fibrosis represents the end stage of a no. of heterogeneous conditions and is, to a greater or lesser degree, the hallmark of the interstitial lung diseases. It is characterized by the excessive deposition of extracellular matrix proteins within the pulmonary interstitium leading to the obliteration of functional alveolar units and in many cases, respiratory failure. While a small no. of interstitial lung diseases have known etiologies, most are idiopathic in nature, and of these, idiopathic pulmonary fibrosis is the most common and carries with it an appalling prognosis - median survival from the time of diagnosis is less than 3 years. This reflects the lack of any effective therapy to modify the course of the disease, which in turn is indicative of our incomplete understanding of the pathogenesis of this condition. Current prevailing hypotheses focus on dysregulated epithelial-mesenchymal interactions promoting a cycle of continued epithelial cell injury and fibroblast activation leading to progressive fibrosis. However, it is likely that multiple abnormalities in a myriad of biol. pathways affecting inflammation and wound repair - including matrix regulation, epithelial reconstitution, the coagulation cascade, neovascularization and antioxidant pathways - modulate this defective crosstalk and promote fibrogenesis. This review aims to offer a pathogenetic rationale behind current therapies, briefly outlining previous and ongoing clin. trials, but will focus on recent and exciting advancements in our understanding of the pathogenesis of idiopathic pulmonary fibrosis, which may ultimately lead to the development of novel and effective therapeutic interventions for this devastating condition.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXls1GjtLc%253D&md5=a161ebe75b90c742137e12b92fbeee42

     
364. 364

     Schuppan, D. Liver Fibrosis: Common Mechanisms and Antifibrotic Therapies. Clin. Res. Hepatol. Gastroenterol. 2015, 39, S51– 59,  DOI: 10.1016/j.clinre.2015.05.005

     [Crossref], [PubMed], [CAS], Google Scholar

     364

     Liver fibrosis: Common mechanisms and antifibrotic therapies

     Schuppan, Detlef

     Clinics and Research in Hepatology and Gastroenterology (2015), 39 (Suppl._1), S51-S59CODEN: CRHGAQ; ISSN:2210-7401. (Elsevier Masson SAS)

     Liver fibrosis and in particular cirrhosis have become major endpoints in clin. trials of patients with chronic liver diseases. Here, viral hepatitis, alc. and non-alc. steatohepatitis have become the major etiologies. We have made great progress in our understanding of the mechanisms and the cell biol. of liver fibrosis and have already made the transition from preclin. testing of antifibrotic agents and strategies towards clin. translation. There continues to be an urgent need for specific antifibrotic therapies, despite the advent of highly potent antiviral agents that can even induce regression of advanced fibrosis. This review addresses central mechanisms and cells to be targeted, current antifibrotic drug trials, and the state of non-invasive biomarker development that is key to rapid clin. progress and to a personalized treatment of fibrosis.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtVegu77M&md5=304d9e38d2f9ace07e18d5cd8682a59a

     
365. 365

     Genovese, F.; Manresa, A. A.; Leeming, D. J.; Karsdal, M. A.; Boor, P. The Extracellular Matrix in the Kidney: A Source of Novel Non-Invasive Biomarkers of Kidney Fibrosis?. Fibrog. Tissue Repair 2014, 7, 4,  DOI: 10.1186/1755-1536-7-4

     [Crossref], [PubMed], [CAS], Google Scholar

     365

     The extracellular matrix in the kidney: a source of novel non-invasive biomarkers of kidney fibrosis?

     Genovese, Federica; Manresa, Alba A.; Leeming, Diana Julie; Karsdal, Morten Asser; Boor, Peter

     Fibrogenesis & Tissue Repair (2014), 7 (), 4/1-4/14, 14 pp.CODEN: FTRIBS; ISSN:1755-1536. (BioMed Central Ltd.)

     Interstitial fibrosis is the common endpoint of end-stage chronic kidney disease (CKD) leading to kidney failure. The clin. course of many renal diseases, and thereby of CKD, is highly variable. One of the major challenges in deciding which treatment approach is best suited for a patient but also in the development of new treatments is the lack of markers able to identify and stratify patients with stable vs. progressive disease. At the moment renal biopsy is the only means of diagnosing renal interstitial fibrosis. Novel biomarkers should improve diagnosis of a disease, est. its prognosis and assess the response to treatment, all in a non-invasive manner. Existing markers of CKD do not fully and specifically address these requirements and in particular do not specifically reflect renal fibrosis. The aim of this review is to give an insight of the involvement of the extracellular matrix (ECM) proteins in kidney diseases and as a source of potential novel biomarkers of renal fibrosis. In particular the use of the protein fingerprint technol., that identifies neo-epitopes of ECM proteins generated by proteolytic cleavage by proteases or other post-translational modifications, might identify such novel biomarkers of renal fibrosis.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXjtFyitLY%253D&md5=e1ce57b98ffccf936c1b9da94b01b947

     
366. 366

     Ho, Y. Y.; Lagares, D.; Tager, A. M.; Kapoor, M. Fibrosis–A Lethal Component of Systemic Sclerosis. Nat. Rev. Rheumatol. 2014, 10, 390– 402,  DOI: 10.1038/nrrheum.2014.53

     [Crossref], [PubMed], [CAS], Google Scholar

     366

     Fibrosis-a lethal component of systemic sclerosis

     Ho, Yuen Yee; Lagares, David; Tager, Andrew M.; Kapoor, Mohit

     Nature Reviews Rheumatology (2014), 10 (7), 390-402CODEN: NRRACB; ISSN:1759-4790. (Nature Publishing Group)

     A review. Fibrosis is a pathol. process characterized by excessive accumulation of connective tissue components in an organ or tissue. Fibrosis is produced by deregulated wound healing in response to chronic tissue injury or chronic inflammation, the hallmarks of rheumatic diseases. Progressive fibrosis, which distorts tissue architecture and results in progressive loss of organ function, is now recognized to be one of the major causes of morbidity and mortality in individuals with one of the most lethal rheumatic disease, systemic sclerosis (SSc). In this Review, we discuss the pathol. role of fibrosis in SSc. We discuss the involvement of endothelium and pericyte activation, aberrant immune responses, endoplasmic reticulum stress and chronic tissue injury in the initiation of fibrosis in SSc. We then discuss fibroblast activation and myofibroblast differentiation that occurs in response to these initiating processes and is responsible for excessive accumulation of extracellular matrix. Finally, we discuss the chem. and mech. signals that drive fibroblast activation and myofibroblast differentiation, which could serve as targets for new therapies for fibrosis in SSc.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXmvV2hu7s%253D&md5=1b9a8a7aab0ca5ea4ee2ee310189f86d

     
367. 367

     Dulai, P. S.; Singh, S.; Patel, J.; Soni, M.; Prokop, L. J.; Younossi, Z.; Sebastiani, G.; Ekstedt, M.; Hagstrom, H.; Nasr, P.; Stal, P.; Wong, V. W.; Kechagias, S.; Hultcrantz, R.; Loomba, R. Increased Risk of Mortality by Fibrosis Stage in Nonalcoholic Fatty Liver Disease: Systematic Review and Meta-Analysis. Hepatology 2017, 65, 1557– 1565,  DOI: 10.1002/hep.29085

     [Crossref], [PubMed], [CAS], Google Scholar

     367

     Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease: Systematic review and meta-analysis

     Dulai, Parambir S.; Singh, Siddharth; Patel, Janki; Soni, Meera; Prokop, Larry J.; Younossi, Zobair; Sebastiani, Giada; Ekstedt, Mattias; Hagstrom, Hannes; Nasr, Patrik; Stal, Per; Wong, Vincent Wai-Sun; Kechagias, Stergios; Hultcrantz, Rolf; Loomba, Rohit

     Hepatology (Hoboken, NJ, United States) (2017), 65 (5), 1557-1565CODEN: HPTLD9; ISSN:0270-9139. (John Wiley & Sons, Inc.)

     Liver fibrosis is the most important predictor of mortality in nonalcoholic fatty liver disease (NAFLD). Quant. risk of mortality by fibrosis stage has not been systematically evaluated. We aimed to quantify the fibrosis stage-specific risk of all-cause and liver-related mortality in NAFLD. Through a systematic review and meta-anal., we identified five adult NAFLD cohort studies reporting fibrosis stage-specific mortality (0-4). Using fibrosis stage 0 as a ref. population, fibrosis stage-specific mortality rate ratios (MRRs) with 95% confidence intervals (CIs) for all-cause and liver-related mortality were estd. The study is reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Included were 1,495 NAFLD patients with 17,452 patient years of follow-up. Compared to NAFLD patients with no fibrosis (stage 0), NAFLD patients with fibrosis were at an increased risk for all-cause mortality, and this risk increased with increases in the stage of fibrosis: stage 1, MRR = 1.58 (95% CI 1.19-2.11); stage 2, MRR = 2.52 (95% CI 1.85-3.42); stage 3, MRR = 3.48 (95% CI 2.51-4.83); and stage 4, MRR = 6.40 (95% CI 4.11-9.95). The results were more pronounced as the risk of liver-related mortality increased exponentially with each increase in the stage of fibrosis: stage 1, MRR = 1.41 (95% CI 0.17-11.95); stage 2, MRR = 9.57 (95% CI 1.67-54.93); stage 3, MRR = 16.69 (95% CI 2.92-95.36); and stage 4, MRR = 42.30 (95% CI 3.51-510.34). Limitations of the study include an inability to adjust for comorbid conditions or demographics known to impact fibrosis progression in NAFLD and the inclusion of patients with simple steatosis and nonalcoholic steatohepatitis without fibrosis in the ref. comparison group. Conclusion: The risk of liver-related mortality increases exponentially with increase in fibrosis stage; these data have important implications in assessing the utility of each stage and benefits of regression of fibrosis from one stage to another. (Hepatol. 2017;65:1557-1565).

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXmt12ksLo%253D&md5=75659cf27e967d0b19a988b136169619

     
368. 368

     Moon, H. J.; Finney, J.; Ronnebaum, T.; Mure, M. Human Lysyl Oxidase-Like 2. Bioorg. Chem. 2014, 57, 231– 241,  DOI: 10.1016/j.bioorg.2014.07.003

     [Crossref], [PubMed], [CAS], Google Scholar

     368

     Human lysyl oxidase-like 2

     Moon, Hee-Jung; Finney, Joel; Ronnebaum, Trey; Mure, Minae

     Bioorganic Chemistry (2014), 57 (), 231-241CODEN: BOCMBM; ISSN:0045-2068. (Elsevier B.V.)

     A review. Lysyl oxidase like-2 (LOXL2) belongs to the lysyl oxidase (LOX) family, which comprises Cu2+- and lysine tyrosylquinone (LTQ)-dependent amine oxidases. LOXL2 is proposed to function similarly to LOX in the extracellular matrix (ECM) by promoting crosslinking of collagen and elastin. LOXL2 has also been proposed to regulate extracellular and intracellular cell signaling pathways. Dysregulation of LOXL2 has been linked to many diseases, including cancer, pro-oncogenic angiogenesis, fibrosis and heart diseases. In this review, we will give an overview of the current understandings and hypotheses regarding the mol. functions of LOXL2.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXht12ntbrE&md5=b6ded89bd69abcef395afb909f626b0e

     
369. 369

     Barry-Hamilton, V.; Spangler, R.; Marshall, D.; McCauley, S.; Rodriguez, H. M.; Oyasu, M.; Mikels, A.; Vaysberg, M.; Ghermazien, H.; Wai, C.; Garcia, C. A.; Velayo, A. C.; Jorgensen, B.; Biermann, D.; Tsai, D.; Green, J.; Zaffryar-Eilot, S.; Holzer, A.; Ogg, S.; Thai, D.; Neufeld, G.; Van Vlasselaer, P.; Smith, V. Allosteric Inhibition of Lysyl Oxidase-Like-2 Impedes the Development of a Pathologic Microenvironment. Nat. Med. 2010, 16, 1009– 1017,  DOI: 10.1038/nm.2208

     [Crossref], [PubMed], [CAS], Google Scholar

     369

     Allosteric inhibition of lysyl oxidase-like-2 impedes the development of a pathologic microenvironment

     Barry-Hamilton, Vivian; Spangler, Rhyannon; Marshall, Derek; McCauley, Scott; Rodriguez, Hector M.; Oyasu, Miho; Mikels, Amanda; Vaysberg, Maria; Ghermazien, Haben; Wai, Carol; Garcia, Carlos A.; Velayo, Arleene C.; Jorgensen, Brett; Biermann, Donna; Tsai, Daniel; Green, Jennifer; Zaffryar-Eilot, Shelly; Holzer, Alison; Ogg, Scott; Thai, Dung; Neufeld, Gera; Van Vlasselaer, Peter; Smith, Victoria

     Nature Medicine (New York, NY, United States) (2010), 16 (9), 1009-1017CODEN: NAMEFI; ISSN:1078-8956. (Nature Publishing Group)

     We have identified a new role for the matrix enzyme lysyl oxidase-like-2 (LOXL2) in the creation and maintenance of the pathol. microenvironment of cancer and fibrotic disease. Our anal. of biopsies from human tumors and fibrotic lung and liver tissues revealed an increase in LOXL2 in disease-assocd. stroma and limited expression in healthy tissues. Targeting LOXL2 with an inhibitory monoclonal antibody (AB0023) was efficacious in both primary and metastatic xenograft models of cancer, as well as in liver and lung fibrosis models. Inhibition of LOXL2 resulted in a marked redn. in activated fibroblasts, desmoplasia and endothelial cells, decreased prodn. of growth factors and cytokines and decreased transforming growth factor-β (TGF-β) pathway signaling. AB0023 outperformed the small-mol. lysyl oxidase inhibitor β-aminopropionitrile. The efficacy and safety of LOXL2-specific AB0023 represents a new therapeutic approach with broad applicability in oncol. and fibrotic diseases.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtFWksrvF&md5=7e69cbf26c2985ad03fbb620538a5f04

     
370. 370

     Ikenaga, N.; Peng, Z. W.; Vaid, K. A.; Liu, S. B.; Yoshida, S.; Sverdlov, D. Y.; Mikels-Vigdal, A.; Smith, V.; Schuppan, D.; Popov, Y. V. Selective Targeting of Lysyl Oxidase-Like 2 (LOXL2) Suppresses Hepatic Fibrosis Progression and Accelerates its Reversal. Gut 2017, 66, 1697– 1708,  DOI: 10.1136/gutjnl-2016-312473

     [Crossref], [PubMed], [CAS], Google Scholar

     370

     Selective targeting of lysyl oxidase-like 2 (LOXL2) suppresses hepatic fibrosis progression and accelerates its reversal

     Ikenaga, Naoki; Peng, Zhen-Wei; Vaid, Kahini A.; Liu, Susan B.; Yoshida, Shuhei; Sverdlov, Deanna Y.; Mikels-Vigdal, Amanda; Smith, Victoria; Schuppan, Detlef; Popov, Yury V.

     Gut (2017), 66 (9), 1697-1709CODEN: GUTTAK; ISSN:0017-5749. (BMJ Publishing Group)

     Background/Aims: We studied the role of lysyl oxidase-like 2 (LOXL2) in collagen crosslinking and hepatic progenitor cell (HPC) differentiation, and the therapeutic efficacy of a LOXL2-blocking monoclonal antibody on liver fibrosis progression/reversal in mice. Methods: Anti-LOXL2 antibody, control antilysyl oxidase antibody or placebo was administered during thioacetamide (TAA)-induced fibrosis progression or during recovery. Therapeutic efficacy in biliary fibrosis was tested in BALB/c.Mdr2-/- and 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-fed mice. Collagen crosslinking, fibrosis progression and reversal were assessed histol. and biochem. HPC differentiation was studied in primary EpCAM(+)liver cells in vitro. Results: LOXL2 was virtually absent from healthy but strongly induced in fibrotic liver, with predominant localization within fibrotic septa. Delayed anti-LOXL2 treatment of active TAA fibrosis significantly reduced collagen crosslinking and histol. signs of bridging fibrosis, with a 53% redn. in morphometric collagen deposition. In established TAA fibrosis, LOXL2 inhibition promoted fibrosis reversal, with enhanced splitting and thinning of fibrotic septa, and a 45% decrease in collagen area at 4 wk of recovery. In the Mdr2-/- and DDC-induced models of biliary fibrosis, anti-LOXL2 antibody similarly achieved significant antifibrotic efficacy and suppressed the ductular reaction, while hepatocyte replication increased. Blocking LOXL2 had a profound direct effect on primary EpCAM(+)HPC behavior in vitro, promoting their differentiation towards hepatocytes, while inhibiting ductal cell lineage commitment. Conclusions: LOXL2 mediates collagen crosslinking and fibrotic matrix stabilization during liver fibrosis, and independently promotes fibrogenic HPC differentiation. By blocking these two convergent profibrotic pathways, therapeutic LOXL2 inhibition attenuates both parenchymal and biliary fibrosis and promotes fibrosis reversal.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitVShurvP&md5=1af0e332c38eb1850cf1fa9d613fb6be

     
371. 371

     Chen, L.; Li, S.; Li, W. LOX/LOXL in Pulmonary Fibrosis: Potential Therapeutic Targets. J. Drug Target. 2019, 27, 790– 796,  DOI: 10.1080/1061186X.2018.1550649

     [Crossref], [PubMed], [CAS], Google Scholar

     371

     LOX/LOXL in pulmonary fibrosis: potential therapeutic targets

     Chen, Lijun; Li, Shifeng; Li, Wande

     Journal of Drug Targeting (2019), 27 (7), 790-796CODEN: JDTAEH; ISSN:1026-7158. (Taylor & Francis Ltd.)

     Lysyl oxidase (LOX) and lysyl oxidase-like proteins (LOXL), a family of extracellular matrix (ECM) crosslinking enzymes that have been recognized as playing an important role in fibrogenesis for more than 40years, are logical targets for antifibrotic treatments. Pulmonary fibrosis, esp. idiopathic pulmonary fibrosis (IPF), is a progressive and lethal disease characterised by excessive deposition of ECM in the lung parenchyma. In this review, we discuss the current clin. approaches for IPF and review members of LOX family-LOX, LOXL1, LOXL2, LOXL3 and LOXL4 in IPF patients and in animal models of bleomycin-induced pulmonary fibrosis. Although these findings are controversial and require further validation, LOX/LOXL1/LOXL2 as potential therapeutic targets for IPF deserve continued attention. So far to our knowledge, LOXL3 or LOXL4 has not clearly shown specific therapeutic potential.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXisVWju7bI&md5=7296afd86e56f665779a4f3cd390a160

     
372. 372

     Puente, A.; Fortea, J. I.; Cabezas, J.; Arias Loste, M. T.; Iruzubieta, P.; Llerena, S.; Huelin, P.; Fabrega, E.; Crespo, J. LOXL2-A New Target in Antifibrogenic Therapy?. Int. J. Mol. Sci. 2019, 20, 1634,  DOI: 10.3390/ijms20071634

     [Crossref], [CAS], Google Scholar

     372

     LOXL2-a new target in antifibrogenic therapy?

     Puente, Angela; Fortea, Jose Ignacio; Cabezas, Joaquin; Loste, Maria Teresa Arias; Iruzubieta, Paula; Llerena, Susana; Huelin, Patricia; Fabrega, Emilio; Crespo, Javier

     International Journal of Molecular Sciences (2019), 20 (7), 1634CODEN: IJMCFK; ISSN:1422-0067. (MDPI AG)

     A review. The concept of liver fibrosis and cirrhosis being static and therefore irreversible is outdated. Indeed, both human and animal studies have shown that fibrogenesis is a dynamic and potentially reversible process that can be modulated either by stopping its progression and/or by promoting its resoln. Therefore, the study of the mol. mechanisms involved in the pathogenesis of liver fibrosis is crit. for the development of future antifibrotic therapies. The fibrogenesis process, common to all forms of liver injury, is characterized by the increased deposition of extracellular matrix components (EMCs), including collagen, proteoglycans, and glycoproteins (laminin and fibronectin 2). These changes in the compn. of the extracellular matrix components alter their interaction with cell adhesion mols., influencing the modulation of cell functions (growth, migration, and gene expression). Hepatic stellate cells and Kupffer cells (liver macrophages) are the key fibrogenic effectors. The antifibrogenic mechanism starts with the activation of Ly6Chigh macrophages, which can differentiate into macrophages with antifibrogenic action. The research of biochem. changes affecting fibrosis irreversibility has identified lysyl oxidase-like 2 (LOXL2), an enzyme that promotes the network of collagen fibers of the extracellular matrix. LOXL2 inhibition can decrease cell nos., proliferation, colony formations, and cell growth, and it can induce cell cycle arrest and increase apoptosis. The development of a new humanized IgG4 monoclonal antibody against LOXL2 could open the window of a new antifibrogenic treatment. The current therapeutic target in patients with liver cirrhosis should focus (after the eradication of the causal agent) on the development of new antifibrogenic drugs. The development of these drugs must meet three premises: Patient safety, in non-cirrhotic phases, down-staging or at least stabilization and slowing the progression to cirrhosis must be achieved; whereas in the cirrhotic stage, the objective should be to reduce fibrosis and portal pressure.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXosVOksg%253D%253D&md5=11468a9417073b0b2a2cf46086f9b436

     
373. 373

     Harrison, S. A.; Abdelmalek, M. F.; Caldwell, S.; Shiffman, M. L.; Diehl, A. M.; Ghalib, R.; Lawitz, E. J.; Rockey, D. C.; Schall, R. A.; Jia, C.; McColgan, B. J.; McHutchison, J. G.; Subramanian, G. M.; Myers, R. P.; Younossi, Z.; Ratziu, V.; Muir, A. J.; Afdhal, N. H.; Goodman, Z.; Bosch, J.; Sanyal, A. J. Simtuzumab is Ineffective for Patients with Bridging Fibrosis or Compensated Cirrhosis Caused by Nonalcoholic Steatohepatitis. Gastroenterology 2018, 155, 1140– 1153,  DOI: 10.1053/j.gastro.2018.07.006

     [Crossref], [PubMed], [CAS], Google Scholar

     373

     Simtuzumab Is Ineffective for Patients With Bridging Fibrosis or Compensated Cirrhosis Caused by Nonalcoholic Steatohepatitis

     Harrison, Stephen A.; Abdelmalek, Manal F.; Caldwell, Stephen; Shiffman, Mitchell L.; Diehl, Anna Mae; Ghalib, Reem; Lawitz, Eric J.; Rockey, Don C.; Schall, Raul Aguilar; Jia, Catherine; McColgan, Bryan J.; McHutchison, John G.; Subramanian, G. Mani; Myers, Robert P.; Younossi, Zobair; Ratziu, Vlad; Muir, Andrew J.; Afdhal, Nezam H.; Goodman, Zachary; Bosch, Jaime; Sanyal, Arun J.

     Gastroenterology (2018), 155 (4), 1140-1153CODEN: GASTAB; ISSN:0016-5085. (Elsevier)

     Lysyl oxidase-like 2 contributes to fibrogenesis by catalyzing cross-linkage of collagen. We evaluated the safety and efficacy of simtuzumab, a monoclonal antibody against lysyl oxidase-like 2, in two phase 2b trials of patients with advanced fibrosis caused by nonalcoholic steatohepatitis. We performed a double-blind study of 219 patients with bridging fibrosis caused by nonalcoholic steatohepatitis who were randomly assigned (1:1:1) to groups given weekly s.c. injections of simtuzumab (75 or 125 mg) or placebo for a planned duration of 240 wk. We performed a sep. study of 258 patients with compensated cirrhosis randomly assigned (1:1:1) to groups given i.v. infusions of simtuzumab (200 or 700 mg) or placebo every other week. The studies were performed from Jan. 2013 through July 2014 at 80 sites in North America and Europe. Biopsy specimens were collected and analyzed at screening and at weeks 48 and 96; clin. information and serum levels of fibrosis biomarkers were collected throughout the study. The primary end point was change from baseline to week 96 in hepatic collagen content, measured by morphometry of liver specimens, in patients with bridging fibrosis; for patients with cirrhosis, the primary end point was change in hepatic venous pressure gradient from baseline to week 96. The 2 studies were stopped after week 96 because of lack of efficacy. All 3 groups of patients with bridging fibrosis-including those given placebo-had significant decreases in hepatic collagen content, but there was no statistically significant difference in decrease between patients receiving simtuzumab 75 mg and those receiving placebo (-0.2%, 95% confidence interval [CI] -1.3 to 1.0, P = .77) or between patients receiving simtuzumab 125 mg and those receiving placebo (-0.4%, 95% CI -1.5 to 0.8, P = .52). In patients with cirrhosis, the mean difference in hepatic venous pressure gradient between the 2 simtuzumab groups and the placebo group was 0.1 mm Hg (95% CI -1.2 to 1.5, P = .84 for 200 mg; 95% CI -1.2 to 1.4, P = .88 for 700 mg). Simtuzumab did not significantly decrease fibrosis stage, progression to cirrhosis in patients with bridging fibrosis, or liver-related clin. events in patients with cirrhosis. Rates of adverse events were similar among groups. In two phase 2b trials of patients with bridging fibrosis or compensated cirrhosis assocd. with nonalcoholic steatohepatitis, simtuzumab was ineffective in decreasing hepatic collagen content or hepatic venous pressure gradient, resp. Clinicaltrials.govNCT01672866 and NCT01672879.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhvVOhu7bL&md5=192b0e83ead82aebc2f6303dd948a79a

     
374. 374

     Muir, A. J.; Levy, C.; Janssen, H. L. A.; Montano-Loza, A. J.; Shiffman, M. L.; Caldwell, S.; Luketic, V.; Ding, D.; Jia, C.; McColgan, B. J.; McHutchison, J. G.; Mani Subramanian, G.; Myers, R. P.; Manns, M.; Chapman, R.; Afdhal, N. H.; Goodman, Z.; Eksteen, B.; Bowlus, C. L. Simtuzumab for Primary Sclerosing Cholangitis: Phase 2 Study Results with Insights on the Natural History of the Disease. Hepatology 2019, 69, 684– 698,  DOI: 10.1002/hep.30237

     [Crossref], [PubMed], [CAS], Google Scholar

     374

     Simtuzumab for Primary Sclerosing Cholangitis: Phase 2 Study Results With Insights on the Natural History of the Disease

     Muir, Andrew J.; Levy, Cynthia; Janssen, Harry L. A.; Montano-Loza, Aldo J.; Shiffman, Mitchell L.; Caldwell, Stephen; Luketic, Velimir; Ding, Dora; Jia, Catherine; McColgan, Bryan J.; McHutchison, John G.; Mani Subramanian, G.; Myers, Robert P.; Manns, Michael; Chapman, Roger; Afdhal, Nezam H.; Goodman, Zachary; Eksteen, Bertus; Bowlus, Christopher L.

     Hepatology (Hoboken, NJ, United States) (2019), 69 (2), 684-698CODEN: HPTLD9; ISSN:0270-9139. (John Wiley & Sons, Inc.)

     Lysyl oxidase like-2 (LOXL2) plays a central role in fibrogenesis and is elevated in the serum and liver of patients with primary sclerosing cholangitis (PSC). We evaluated the safety and efficacy of simtuzumab, a monoclonal antibody directed against LOXL2, in patients with PSC. Patients with compensated liver disease caused by PSC were randomized 1:1:1 to receive weekly s.c. injections of simtuzumab 75 mg, simtuzumab 125 mg, or placebo for 96 wk. The primary efficacy endpoint was mean change in hepatic collagen content assessed by morphometry between baseline and week 96. Addnl. endpoints included change in Ishak fibrosis stage and the frequency of PSC-related clin. events. Overall, 234 patients were randomized and started treatment. At week 96, the mean change from baseline in hepatic collagen content was -0.5% for patients receiving simtuzumab 75 mg (P = 0.73 vs. placebo), +0.5% for patients receiving simtuzumab 125 mg (P = 0.33 vs. placebo), and 0.0 for patients receiving placebo. Compared with placebo, neither dose of simtuzumab led to significant redns. in Ishak fibrosis stage, progression to cirrhosis, or frequency of clin. events. Overall, 80 (34%) patients had fibrosis progression and 47 (20%) experienced PSC-related clin. events. In a multivariate model of baseline factors, PSC-related clin. events were more frequent in patients with advanced fibrosis (hazard ratio [HR], 2.03; 95% confidence interval [CI], 1.02-4.06; P = 0.045), higher alk. phosphatase (HR per 10 U/L, 1.01; 95% CI, 1.00-1.02; P = 0.015), and higher enhanced liver fibrosis score (HR per unit, 1.26; 95% CI, 0.98-1.61; P = 0.073). Overall, rates of adverse events and lab. abnormalities were similar between groups. Conclusion: Treatment with the LOXL2 inhibitor simtuzumab for 96 wk did not provide clin. benefit in patients with PSC.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhvFKitro%253D&md5=65dd8794dbc83ec40521c968c742612f

     
375. 375

     Pischon, N.; Maki, J. M.; Weisshaupt, P.; Heng, N.; Palamakumbura, A. H.; N’Guessan, P.; Ding, A.; Radlanski, R.; Renz, H.; Bronckers, T. A.; Myllyharju, J.; Kielbassa, A. M.; Kleber, B. M.; Bernimoulin, J. P.; Trackman, P. C. Lysyl Oxidase (Lox) Gene Deficiency Affects Osteoblastic Phenotype. Calcif. Tissue Int. 2009, 85, 119– 126,  DOI: 10.1007/s00223-009-9252-8

     [Crossref], [PubMed], [CAS], Google Scholar

     375

     Lysyl Oxidase (Lox) Gene Deficiency Affects Osteoblastic Phenotype

     Pischon, N.; Maeki, J. M.; Weisshaupt, P.; Heng, N.; Palamakumbura, A. H.; N'Guessan, P.; Ding, A.; Radlanski, R.; Renz, H.; Bronckers, T. A. L. J. J.; Myllyharju, J.; Kielbassa, A. M.; Kleber, B. M.; Bernimoulin, J.-P.; Trackman, P. C.

     Calcified Tissue International (2009), 85 (2), 119-126CODEN: CTINDZ; ISSN:0171-967X. (Springer)

     Lysyl oxidase (LOX) catalyzes crosslinking of elastin and collagen, which is essential for the structural integrity and function of bone tissue. The present study examd. the role of Lox gene deficiency for the osteoblast phenotype in primary calvarial osteoblasts from E18.5 Lox knockout (Lox -/- ) and wild type (wt) (C57BL/6) mice. Next to Lox gene depletion, mRNA expression of Lox isoforms, LOXL1-4, was significantly downregulated in Lox -/- bone tissue. A significant decrease of DNA synthesis of Lox -/- osteoblasts compared to wt was found. Early stages of osteoblastic apoptosis studied by annexin-V binding as well as later stages of DNA fragmentation were not affected. However, mineral nodule formation and osteoblastic differentiation were markedly decreased, as revealed by significant downregulation of osteoblastic markers, type I collagen, bone sialoprotein, and Runx2/Cbfa1.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtVait7%252FI&md5=fab4300b8ff8b116247836bdf6aae915

     
376. 376

     Rowbottom, M. W.; Bain, G.; Calderon, I.; Lasof, T.; Lonergan, D.; Lai, A.; Huang, F.; Darlington, J.; Prodanovich, P.; Santini, A. M.; King, C. D.; Goulet, L.; Shannon, K. E.; Ma, G. L.; Nguyen, K.; MacKenna, D. A.; Evans, J. F.; Hutchinson, J. H. Identification of 4-(Aminomethyl)-6-(trifluoromethyl)-2-(phenoxy)pyridine Derivatives as Potent, Selective, and Orally Efficacious Inhibitors of the Copper-Dependent Amine Oxidase, Lysyl Oxidase-Like 2 (LOXL2). J. Med. Chem. 2017, 60, 4403– 4423,  DOI: 10.1021/acs.jmedchem.7b00345

     [ACS Full Text ], [CAS], Google Scholar

     376

     Identification of 4-(Aminomethyl)-6-(trifluoromethyl)-2-(phenoxy)pyridine Derivatives as Potent, Selective, and Orally Efficacious Inhibitors of the Copper-Dependent Amine Oxidase, Lysyl Oxidase-Like 2 (LOXL2)

     Rowbottom, Martin W.; Bain, Gretchen; Calderon, Imelda; Lasof, Taylor; Lonergan, David; Lai, Andiliy; Huang, Fei; Darlington, Janice; Prodanovich, Patricia; Santini, Angelina M.; King, Christopher D.; Goulet, Lance; Shannon, Kristen E.; Ma, Gina L.; Nguyen, Katherine; MacKenna, Deidre A.; Evans, Jilly F.; Hutchinson, John H.

     Journal of Medicinal Chemistry (2017), 60 (10), 4403-4423CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

     LOXL2 catalyzes the oxidative deamination of ε-amines of lysine and hydroxylysine residues within collagen and elastin, generating reactive aldehydes (allysine). Condensation with other allysines or lysines drives the formation of inter- and intramol. cross-linkages, a process crit. for the remodeling of the ECM. Dysregulation of this process can lead to fibrosis, and LOXL2 is known to be upregulated in fibrotic tissue. Small-mols. that directly inhibit LOXL2 catalytic activity represent a useful option for the treatment of fibrosis. Herein, the authors describe optimization of an initial hit, resulting in identification of racemic I, a potent irreversible inhibitor of LOXL2 that is highly selective over LOX and other amine oxidases. Oral administration of I significantly reduced fibrosis in a 14-day mouse lung bleomycin model. The (R,R)-enantiomer of I (PAT-1251) was selected as the clin. compd. which has progressed into healthy volunteer Phase 1 trials, making it the "first-in-class" small-mol. LOXL2 inhibitor to enter clin. development. KEY LOXL2 inhibitor.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXntFSksrs%253D&md5=c71db3046b5ed711043b39181fdf87c9

     
377. 377

     Pharmakea Therapeutics http://www.pharmakea.com/index.php?%20option=com_content&view=article&id=41&Itemid=231 (accessed Sept 25, 2019).

     Google Scholar

     There is no corresponding record for this reference.

     
378. 378

     Schilter, H.; Findlay, A. D.; Perryman, L.; Yow, T. T.; Moses, J.; Zahoor, A.; Turner, C. I.; Deodhar, M.; Foot, J. S.; Zhou, W.; Greco, A.; Joshi, A.; Rayner, B.; Townsend, S.; Buson, A.; Jarolimek, W. The Lysyl Oxidase Like 2/3 Enzymatic Inhibitor, PXS-5153A, Reduces Crosslinks and Ameliorates Fibrosis. J. Cell. Mol. Med. 2018, 23, 1759– 1770,  DOI: 10.1111/jcmm.14074

     [Crossref], [PubMed], Google Scholar

     There is no corresponding record for this reference.

     
379. 379

     Findlay, A. D.; Foot, J. S.; Buson, A.; Deodhar, M.; Jarnicki, A. G.; Hansbro, P. M.; Liu, G.; Schilter, H.; Turner, C. I.; Zhou, W.; Jarolimek, W. Identification and Optimization of Mechanism-Based Fluoroallylamine Inhibitors of Lysyl Oxidase-like 2/3. J. Med. Chem. 2019, 62, 9874– 9889,  DOI: 10.1021/acs.jmedchem.9b01283

     [ACS Full Text ], [CAS], Google Scholar

     379

     Identification and Optimization of Mechanism-Based Fluoroallylamine Inhibitors of Lysyl Oxidase-like 2/3

     Findlay, Alison D.; Foot, Jonathan S.; Buson, Alberto; Deodhar, Mandar; Jarnicki, Andrew G.; Hansbro, Philip M.; Liu, Gang; Schilter, Heidi; Turner, Craig I.; Zhou, Wenbin; Jarolimek, Wolfgang

     Journal of Medicinal Chemistry (2019), 62 (21), 9874-9889CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

     Lysyl oxidase-like 2 (LOXL2) is a secreted enzyme that catalyzes the formation of cross-links in extracellular matrix proteins, namely, collagen and elastin, and is indicated in fibrotic diseases. Herein, we report the identification and subsequent optimization of a series of indole-based fluoroallylamine inhibitors of LOXL2. The result of this medicinal chem. campaign is PXS-5120A (12k), a potent, irreversible inhibitor that is >300-fold selective for LOXL2 over LOX. PXS-5120A also shows potent inhibition of LOXL3, an emerging therapeutic target for lung fibrosis. Key to the development of this compd. was the utilization of a compd. oxidn. assay. PXS-5120A was optimized to show negligible substrate activity in vitro for related amine oxidase family members, leading to metabolic stability. PXS-5120A, in a pro-drug form (PXS-5129A, 12o), displayed anti-fibrotic activity in models of liver and lung fibrosis, thus confirming LOXL2 as an important target in diseases where collagen crosslinking is implicated.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhvFSjurvK&md5=bf560c1af3b6f90b80f4e44fe140c2ff

     
380. 380

     Takakura, K.; Koido, S.; Fujii, M.; Hashiguchi, T.; Shibazaki, Y.; Yoneyama, H.; Katagi, H.; Kajihara, M.; Misawa, T.; Homma, S.; Ohkusa, T.; Tajiri, H. Characterization of Non-Alcoholic Steatohepatitis-Derived Hepatocellular Carcinoma as a Human Stratification Model in Mice. Anticancer Res. 2014, 34, 4849– 4855

     [PubMed], [CAS], Google Scholar

     380

     Characterization of non-alcoholic steatohepatitis-derived hepatocellular carcinoma as a human stratification model in mice

     Takakura Kazuki; Koido Shigeo; Kajihara Mikio; Ohkusa Toshifumi; Fujii Masato; Hashiguchi Taishi; Shibazaki Yuichiro; Yoneyama Hiroyuki; Katagi Hiroaki; Misawa Takeyuki; Homma Sadamu; Tajiri Hisao

     Anticancer research (2014), 34 (9), 4849-55 ISSN:.

     The therapeutic strategy against hepatocellular carcinoma (HCC) is determined by tumor stage and liver function. Improvements of stratification contribute to extending the survival of patients. However, stratification has been attributed little attention in animal models largely due to the lack of suitable models. Herein we showed that the recently-reported, non-alcoholic steatohepatitis-derived HCC model (STAM model) is the first murine model in which the concept of human stratification is applicable by demonstrating the following features: (i) at least 4 detectable tumor nodules; (ii) average tumor growth rate of 150 % from 16 to 20 weeks of age; (iii) no visible metastasis; and (iv) relatively preserved liver function. These observations suggested that HCC in STAM mice is equivalent to stages B to C of the Barcelona Clinic Liver Cancer (BCLC) staging system for humans. Application of the stratification concept to experimental animals will create new avenues to establish pharmacological intervention against HCC.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2M%252FpsFOnsQ%253D%253D&md5=6ecd290cb2f2d453b605da302d2eade2

     
381. 381

     Pharmaxis http://www.pharmaxis.com.au/product-pipeline/amine-oxidase-platform/loxloxl2/ (accessed Sept 25, 2019).

     Google Scholar

     There is no corresponding record for this reference.

     
382. 382

     Di Lella, S.; Sundblad, V.; Cerliani, J. P.; Guardia, C. M.; Estrin, D. A.; Vasta, G. R.; Rabinovich, G. A. When Galectins Recognize Glycans: From Biochemistry to Physiology and Back Again. Biochemistry 2011, 50, 7842– 7857,  DOI: 10.1021/bi201121m

     [ACS Full Text ], [CAS], Google Scholar

     382

     When galectins recognize glycans: From biochemistry to physiology and back again

     Di Lella, Santiago; Sundblad, Victoria; Cerliani, Juan P.; Guardia, CarlosM.; Estrin, Dario A.; Vasta, Gerardo R.; Rabinovich, Gabriel A.

     Biochemistry (2011), 50 (37), 7842-7857CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)

     A review. In the past decade, increasing efforts have been devoted to the study of galectins, a family of evolutionarily conserved glycan-binding proteins with multifunctional properties. Galectins function, either intracellularly or extracellularly, as key biol. mediators capable of monitoring changes occurring on the cell surface during fundamental biol. processes such as cellular communication, inflammation, development, and differentiation. Their highly conserved structures, exquisite carbohydrate specificity, and ability to modulate a broad spectrum of biol. processes have captivated a wide range of scientists from a wide spectrum of disciplines, including biochem., biophysics, cell biol., and physiol. However, in spite of enormous efforts to dissect the functions and properties of these glycan-binding proteins, limited information about how structural and biochem. aspects of these proteins can influence biol. functions is available. Here, the authors aimed to integrate structural, biochem., and functional aspects of this bewildering and ancient family of glycan-binding proteins and discuss their implications in physiol. and pathol. settings.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtVOktrfI&md5=4f49f1880ba08056ce2bb6f24e750578

     
383. 383

     Johannes, L.; Jacob, R.; Leffler, H. Galectins at a glance. J. Cell Sci. 2018, 131, jcs208884,  DOI: 10.1242/jcs.208884

     [Crossref], [PubMed], Google Scholar

     There is no corresponding record for this reference.

     
384. 384

     Chan, Y. C.; Lin, H. Y.; Tu, Z.; Kuo, Y. H.; Hsu, S. D.; Lin, C. H. Dissecting the Structure-Activity Relationship of Galectin-Ligand Interactions. Int. J. Mol. Sci. 2018, 19, 392,  DOI: 10.3390/ijms19020392

     [Crossref], [PubMed], Google Scholar

     There is no corresponding record for this reference.

     
385. 385

     Hsu, D. K.; Dowling, C. A.; Jeng, K. C.; Chen, J. T.; Yang, R. Y.; Liu, F. T. Galectin-3 Expression is Induced in Cirrhotic Liver and Hepatocellular Carcinoma. Int. J. Cancer 1999, 81, 519– 526,  DOI: 10.1002/(SICI)1097-0215(19990517)81:4<519::AID-IJC3>3.0.CO;2-0

     [Crossref], [PubMed], [CAS], Google Scholar

     385

     Galectin-3 expression is induced in cirrhotic liver and hepatocellular carcinoma

     Hsu D K; Dowling C A; Jeng K C; Chen J T; Yang R Y; Liu F T

     International journal of cancer (1999), 81 (4), 519-26 ISSN:0020-7136.

     Galectins are a family of beta-galactoside-binding animal lectins. In particular, a widely studied member galectin-3, previously designated as epsilonBP, CBP35, Mac-2, L-29 and L-34, has been associated with assorted processes such as cell growth, tumor transformation and metastasis. Galectin-3 is expressed in various tissues and organs but is significantly absent in normal hepatocytes. However, evaluation of patient liver biopsies for galectin-3 expression resulted in the finding that hepatocellular carcinoma (HCC) frequently expressed significant levels of this lectin (76% immunohistochemically positive). Further investigation revealed that galectin-3 expression in HCC is independent of whether the patient had prior hepatitis B virus infection: 14 of 18 HCC cases from HBV- patients, and 5 of 7 cases from HBV patients demonstrated positive galectin-3 immunohistochemistry. However, co-transfection studies using a galectin-3 promoter construct and an HBV-X protein (HBV-X) expression vector demonstrated that galectin-3 expression can occur through transactivation of the lectin promoter by HBV-X. Based on presently known properties of this lectin, it is possible that deregulated expression of galectin-3 can result in tumor transformation and invasiveness, or confer propensity for tumor cell survival. In addition, galectin-3 was abundantly expressed in cirrhotic liver in peripheral distribution within regenerating nodules. Such galectin-3 expression in rapidly proliferating hepatocytes in cirrhotic liver may be a result of the high mitotic index. Alternatively, it is possible that proliferating cells expressing galectin-3 are in the process of being transformed, thus indicating an early neoplastic event.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK1M3jvF2ntg%253D%253D&md5=e2c89f10600446167bdc081b0b5fbbf5

     
386. 386

     Henderson, N. C.; Mackinnon, A. C.; Farnworth, S. L.; Poirier, F.; Russo, F. P.; Iredale, J. P.; Haslett, C.; Simpson, K. J.; Sethi, T. Galectin-3 Regulates Myofibroblast Activation and Hepatic Fibrosis. Proc. Natl. Acad. Sci. U. S. A. 2006, 103, 5060– 5065,  DOI: 10.1073/pnas.0511167103

     [Crossref], [PubMed], [CAS], Google Scholar

     386

     Galectin-3 regulates myofibroblast activation and hepatic fibrosis

     Henderson, Neil C.; Mackinnon, Alison C.; Farnworth, Sarah L.; Poirier, Francoise; Russo, Francesco P.; Iredale, John P.; Haslett, Christopher; Simpson, Kenneth J.; Sethi, Tariq

     Proceedings of the National Academy of Sciences of the United States of America (2006), 103 (13), 5060-5065CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)

     Central to fibrogenesis and the scarring of organs is the activation of fibroblasts into matrix-secreting myofibroblasts. We demonstrate that Galectin-3 expression is up-regulated in established human fibrotic liver disease and is temporally and spatially related to the induction and resoln. of exptl. hepatic fibrosis. Disruption of the Galectin-3 gene blocks myofibroblast activation and procollagen (I) expression in vitro and in vivo, markedly attenuating liver fibrosis. Addn. of exogenous recombinant Galectin-3 in vitro reversed this abnormality. The redn. in hepatic fibrosis obsd. in the Galectin-3-/- mouse occurred despite equiv. liver injury and inflammation, and similar tissue expression of TGF-β. TGF-β failed to transactivate Galectin-3-/- hepatic stellate cells, in contrast with WT hepatic stellate cells; however, TGF-β-stimulated Smad-2 and -3 activation was equiv. These data suggest that Galectin-3 is required for TGF-β mediated myofibroblast activation and matrix prodn. Finally, in vivo siRNA knockdown of Galectin-3 inhibited myofibroblast activation after hepatic injury and may therefore provide an alternative therapeutic approach to the prevention and treatment of liver fibrosis.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XjsVGlsbs%253D&md5=b0d59dfa1ca7830acb564df597edd724

     
387. 387

     Jiang, J. X.; Chen, X.; Hsu, D. K.; Baghy, K.; Serizawa, N.; Scott, F.; Takada, Y.; Takada, Y.; Fukada, H.; Chen, J.; Devaraj, S.; Adamson, R.; Liu, F. T.; Torok, N. J. Galectin-3 Modulates Phagocytosis-Induced Stellate Cell Activation and Liver Fibrosis In Vivo. Am. J. Physiol. Gastrointest. Liver Physiol. 2012, 302, G439– 446,  DOI: 10.1152/ajpgi.00257.2011

     [Crossref], [PubMed], Google Scholar

     There is no corresponding record for this reference.

     
388. 388

     Chalasani, N.; Garcia-Tsao, G.; Goodman, Z.; Lawitz, E.; Abdelmalek, M.; Rinella, M.; Ryan, M.; Noureddin, M.; Jue, C.; Pyko, M.; Allgood, A.; Shlevin, H.; Horton, R.; Zomer, E.; Traber, P.; Loomba, R.; Tetri, B.; Sanyal, A.; Harrison, S. A Multicenter, Randomized, Double-Blind, PLB-Controlled Trial of Galectin-3 Inhibitor (GR-MD-02) in Patients with NASH Cirrhosis and Portal Hypertension. Presented at the European Associate for the Study of the Liver International Liver Conference, Paris, France, April 11–15, 2018; LBO-001.

     Google Scholar

     There is no corresponding record for this reference.

     
389. 389

     Galaectin Therapeutics https://investor.galectintherapeutics.com/news-releases/news-release-details/galectin-therapeutics-proceeds-phase-3-development-gr-md-02-nash (accessed Sept 25, 2019).

     Google Scholar

     There is no corresponding record for this reference.

     
390. 390

     Hansen, H. H.; Feigh, M.; Veidal, S. S.; Rigbolt, K. T.; Vrang, N.; Fosgerau, K. Mouse Models of Nonalcoholic Steatohepatitis in Preclinical Drug Development. Drug Discovery Today 2017, 22, 1707– 1718,  DOI: 10.1016/j.drudis.2017.06.007

     [Crossref], [PubMed], [CAS], Google Scholar

     390

     Mouse models of nonalcoholic steatohepatitis in preclinical drug development

     Hansen, Henrik H.; Feigh, Michael; Veidal, Sanne S.; Rigbolt, Kristoffer T.; Vrang, Niels; Fosgerau, Keld

     Drug Discovery Today (2017), 22 (11), 1707-1718CODEN: DDTOFS; ISSN:1359-6446. (Elsevier Ltd.)

     Nonalcoholic fatty liver disease (NAFLD) has become the most common cause of chronic liver disease in the Western world. NAFLD is a complex spectrum of liver diseases ranging from benign hepatic steatosis to its more aggressive necroinflammatory manifestation, nonalcoholic steatohepatitis (NASH). NASH pathogenesis is multifactorial and risk factors are almost identical to those of the metabolic syndrome. This has prompted substantial efforts to identify novel drug therapies for correcting underlying metabolic deficits, and to prevent or alleviate hepatic fibrosis in NASH. Available mouse models of NASH address different aspects of the disease, have varying clin. translatability, and, therefore, also show different utility in drug discovery.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtFClsL7I&md5=a02049b87da953ab1f1731da1064adb1

     
391. 391

     Kristiansen, M. N.; Veidal, S. S.; Rigbolt, K. T.; Tolbol, K. S.; Roth, J. D.; Jelsing, J.; Vrang, N.; Feigh, M. Obese Diet-Induced Mouse Models of Nonalcoholic Steatohepatitis-Tracking Disease by Liver Biopsy. World J. Hepatol. 2016, 8, 673– 684,  DOI: 10.4254/wjh.v8.i16.673

     [Crossref], [PubMed], [CAS], Google Scholar

     391

     Obese diet-induced mouse models of nonalcoholic steatohepatitis-tracking disease by liver biopsy

     Kristiansen Maria Nicoline Baandrup; Veidal Sanne Skovgard; Rigbolt Kristoffer Tobias Gustav; Tolbol Kirstine Sloth; Roth Jonathan David; Jelsing Jacob; Vrang Niels; Feigh Michael

     World journal of hepatology (2016), 8 (16), 673-84 ISSN:1948-5182.

     AIM: To characterize development of diet-induced nonalcoholic steatohepatitis (NASH) by performing liver biopsy in wild-type and genetically obese mice. METHODS: Male wild-type C57BL/6J (C57) mice (DIO-NASH) and male Lep(ob) /Lep(ob) (ob/ob) mice (ob/ob-NASH) were maintained on a diet high in trans-fat (40%), fructose (22%) and cholesterol (2%) for 26 and 12 wk, respectively. A normal chow diet served as control in C57 mice (lean chow) and ob/ob mice (ob/ob chow). After the diet-induction period, mice were liver biopsied and a blinded histological assessment of steatosis and fibrosis was conducted. Mice were then stratified into groups counterbalanced for steatosis score and fibrosis stage and continued on diet and to receive daily PO dosing of vehicle for 8 wk. Global gene expression in liver tissue was assessed by RNA sequencing and bioinformatics. Metabolic parameters, plasma liver enzymes and lipids (total cholesterol, triglycerides) as well as hepatic lipids and collagen content were measured by biochemical analysis. Non-alcoholic fatty liver disease activity score (NAS) (steatosis/inflammation/ballooning degeneration) and fibrosis were scored. Steatosis and fibrosis were also quantified using percent fractional area. RESULTS: Diet-induction for 26 and 12 wk in DIO-NASH and ob/ob-NASH mice, respectively, elicited progressive metabolic perturbations characterized by increased adiposity, total cholesterol and elevated plasma liver enzymes. The diet also induced clear histological features of NASH including hepatosteatosis and fibrosis. Overall, the metabolic NASH phenotype was more pronounced in ob/ob-NASH vs DIO-NASH mice. During the eight week repeated vehicle dosing period, the metabolic phenotype was sustained in DIO-NASH and ob/ob-NASH mice in conjunction with hepatomegaly and increased hepatic lipids and collagen accumulation. Histopathological scoring demonstrated significantly increased NAS of DIO-NASH mice (0 vs 4.7 ± 0.4, P < 0.001 compared to lean chow) and ob/ob-NASH mice (2.4 ± 0.3 vs 6.3 ± 0.2, P < 0.001 compared to ob/ob chow), respectively. Furthermore, fibrosis stage was significantly elevated for DIO-NASH mice (0 vs 1.2 ± 0.2, P < 0.05 compared to lean chow) and ob/ob NASH (0.1 ± 0.1 vs 3.0 ± 0.2, P < 0.001 compared to ob/ob chow). Notably, fibrosis stage was significantly (P < 0.001) increased in ob/ob-NASH mice, when compared to DIO-NASH mice. CONCLUSION: These data introduce the obese diet-induced DIO-NASH and ob/ob-NASH mouse models with biopsy-confirmed individual disease staging as a preclinical platform for evaluation of novel NASH therapeutics.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2s7isVegtA%253D%253D&md5=29f460edcabcd04cdeca8edc975623cb

     
392. 392

     Sanchez-Garrido, M. A.; Brandt, S. J.; Clemmensen, C.; Muller, T. D.; DiMarchi, R. D.; Tschop, M. H. GLP-1/Glucagon Receptor Co-Agonism for Treatment of Obesity. Diabetologia 2017, 60, 1851– 1861,  DOI: 10.1007/s00125-017-4354-8

     [Crossref], [PubMed], [CAS], Google Scholar

     392

     GLP-1/glucagon receptor co-agonism for treatment of obesity

     Sanchez-Garrido, Miguel A.; Brandt, Sara J.; Clemmensen, Christoffer; Mueller, Timo D.; Di Marchi, Richard D.; Tschoep, Matthias H.

     Diabetologia (2017), 60 (10), 1851-1861CODEN: DBTGAJ; ISSN:0012-186X. (Springer)

     Over a relatively short period, obesity and type 2 diabetes have come to represent a large medical and economic burden to global societies. The epidemic rise in the prevalence of obesity has metabolic consequences and is paralleled by an increased occurrence of other diseases, such as diabetes, cancer and cardiovascular complications. Together, obesity and type 2 diabetes constitute one of the more preventable causes of premature death and the identification of novel, safe and effective anti-obesity drugs is of utmost importance. Pharmacol. attempts to treat obesity have had limited success, with notable adverse effects, rendering bariatric surgery as the only current therapy for substantially improving body wt. Novel unimol., multifunctional peptides have emerged as one of the most promising medicinal approaches to enhance metabolic efficacy and restore normal body wt. In this review, we will mainly focus on the discovery and translational relevance of dual agonists that pharmacol. function at the receptors for glucagon and glucagon-like peptide-1. Such peptides have advanced to clin. evaluation and inspired the pursuit of multiple related approaches to achieving polypharmacy within single mols.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXht1Wru7%252FF&md5=ca76fc85634d91bcbdd5ffd239390f28

     
393. 393

     Boehringer Ingelheim - Yuhan https://www.boehringer-ingelheim.com/press-release/collaboration-yuhan-corporation-nash (accessed Dec 18, 2019).

     Google Scholar

     There is no corresponding record for this reference.

     
394. 394

     Hall, K. C.; Bernier, S. G.; Jacobson, S.; Liu, G.; Zhang, P. Y.; Sarno, R.; Catanzano, V.; Currie, M. G.; Masferrer, J. L. sGC Stimulator Praliciguat Suppresses Stellate Cell Fibrotic Transformation and Inhibits Fibrosis and Inflammation in Models of NASH. Proc. Natl. Acad. Sci. U. S. A. 2019, 116, 11057– 11062,  DOI: 10.1073/pnas.1821045116

     [Crossref], [PubMed], [CAS], Google Scholar

     394

     sGC stimulator praliciguat suppresses stellate cell fibrotic transformation and inhibits fibrosis and inflammation in models of NASH

     Hall, Katherine C.; Bernier, Sylvie G.; Jacobson, Sarah; Liu, Guang; Zhang, Ping Y.; Sarno, Renee; Catanzano, Victoria; Currie, Mark G.; Masferrer, Jaime L.

     Proceedings of the National Academy of Sciences of the United States of America (2019), 116 (22), 11057-11062CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)

     Endothelial dysfunction and reduced nitric oxide (NO) signaling are a key element of the pathophysiol. of nonalcoholic steatohepatitis (NASH). Stimulators of sol. guanylate cyclase (sGC) enhance NO signaling; have been shown preclinically to reduce inflammation, fibrosis, and steatosis; and thus have been proposed as potential therapies for NASH and fibrotic liver diseases. Praliciguat, an oral sGC stimulator with extensive distribution to the liver, was used to explore the role of this signaling pathway in NASH. We found that sGC is expressed in hepatic stellate cells and stellate-derived myofibroblasts, but not in hepatocytes. Praliciguat acted directly on isolated hepatic stellate cells to inhibit fibrotic and inflammatory signaling potentially through regulation of AMPK and SMAD7. Using in vivo microdialysis, we demonstrated stimulation of the NO-sGC pathway by praliciguat in both healthy and fibrotic livers. In preclin. models of NASH, praliciguat treatment was assocd. with lower levels of liver fibrosis and lower expression of fibrotic and inflammatory biomarkers. Praliciguat treatment lowered hepatic steatosis and plasma cholesterol levels. The antiinflammatory and antifibrotic effects of praliciguat were recapitulated in human microtissues in vitro. These data provide a plausible cellular basis for the mechanism of action of sGC stimulators and suggest the potential therapeutic utility of praliciguat in the treatment of NASH.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtVChsrvP&md5=11b59f78431c962fec547d46a93f9586

     
395. 395

     Goodman, S. L.; Picard, M. Integrins as Therapeutic Targets. Trends Pharmacol. Sci. 2012, 33, 405– 412,  DOI: 10.1016/j.tips.2012.04.002

     [Crossref], [PubMed], [CAS], Google Scholar

     395

     Integrins as therapeutic targets

     Goodman, Simon L.; Picard, Martin

     Trends in Pharmacological Sciences (2012), 33 (7), 405-412CODEN: TPHSDY; ISSN:0165-6147. (Elsevier Ltd.)

     A review. Integrins are a large family of mols. that are central regulators in multicellular biol. They orchestrate cell-cell and cell-extracellular matrix (ECM) adhesive interactions from embryonic development to mature tissue function. Diverse human pathologies involve integrin adhesion, including thrombotic diseases, inflammation, cancer, fibrosis and infectious diseases. Integrins are exciting pharmacol. targets because they are exposed on the cell surface and are sensitive to pharmacol. blockade, but the scale of current efforts involving integrin therapeutics continues to surprise. Several therapeutics targeting integrins are effective drugs: five have been approved for use in clinic, with combined sales of over $1.5 billion in 2010 (based on company reports from that year). We gathered information from three major drug-trial databases and found that ∼260 anti-integrin drugs have entered clin. trials. Here we overview integrins as drug targets and focus on cancer.

     >> More from SciFinder ^®

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xns1Wnsrs%253D&md5=de62aa87705664ff23af1ad674b47c5a

     
396. 396

     Pliant https://www.prnewswire.com/news-releases/pliant-therapeutics-announces-strategic-collaboration-to-develop-novel-therapies-for-nash-and-fibrotic-diseases-300942572.html (accessed Nov 26, 2019).

     Google Scholar

     There is no corresponding record for this reference.

     
397. 397

     Morphic - Abbvie https://www.prnewswire.com/news-releases/abbvie-and-morphic-therapeutic-announce-collaboration-targeting-fibrotic-diseases-300733319.html (accessed Nov 26, 2019).

     Google Scholar

     There is no corresponding record for this reference.

     
398. 398

     Morphic - Janssen https://morphictx.com/2019/02/21/morphic-therapeutic-enters-into-integrin-research-and-development-collaboration-with-janssen/ (accessed Nov 26, 2019).

     Google Scholar

     There is no corresponding record for this reference.